Chemical compounds

ABSTRACT

Pyridinyl-benzoheterocycyl kinase inhibitor compounds are disclosed. Also disclosed are methods of making such compounds as well as methods of using the same in the treatment of diseases.

BACKGROUND OF THE INVENTION

The present invention relates to pyridinyl-benzoheterocycyl derivatives,compositions and medicaments containing the same, as well as processesfor the preparation and use of such compounds, compositions andmedicaments. Such pyridinyl-benzoheterocycyl derivatives are useful inthe treatment of diseases associated with inappropriate angiogenesis.

The process of angiogenesis is the development of new blood vessels,generally capillaries, from preexisting vasculature. Angiogenesis isdefined as involving: (i) activation of endothelial cells; (ii)increased vascular permeability; (iii) subsequent dissolution of thebasement membrane and extravisation of plasma components leading toformation of a provisional fibrin gel extracellular matrix; (iv)proliferation and mobilization of endothelial cells; (v) reorganizationof mobilized endothelial cells to form functional capillaries; (vi)capillary loop formation; and (vii) deposition of basement membrane andrecruitment of perivascular cells to newly formed vessels. Normalangiogenesis is activated during tissue growth, from embryonicdevelopment through maturity, and then enters a period of relativequiescence during adulthood. Normal angiogenesis is also activatedduring wound healing, and at certain stages of the female reproductivecycle. Inappropriate angiogenesis has been associated with severaldisease states including various retinopathies; ischemic disease;atherosclerosis; chronic inflammatory disorders; and cancer. The role ofangiogenesis in disease states is discussed, for instance, in Fan etal., Trends in Pharmacol. Sci. 16: 54-66; Shawver et al., DDT Vol. 2,No. 2 Feb. 1997; Folkmann, 1995, Nature Medicine 1: 27-31; Colville-Nashand Scott, Ann. Rheum. Dis., 51, 919,1992; Brooks et al., Cell, 79,1157, 1994; Kahlon et al., Can. J. Cardiol. 8, 60, 1992; Folknan, CancerBiol, 3, 65, 1992; Denekamp, Br. J. Rad. 66, 181, 1993; Fidler andEllis, Cell, 79, 185, 1994; O'Reilly et al., Cell, 79, 315, 1994; Ingberet al., Nature, 348, 555, 1990; Friedlander et al., Science, 270, 1500,1995; Peacock et al., J. Exp. Med. 175, 1135, 1992; Peacock et al.,Cell. Immun. 160, 178, 1995; and Taraboletti et al., J. Natl. CancerInst. 87, 293, 1995.

In cancer the growth of solid tumors has been shown to be angiogenesisdependent. (See Folkmann, J., J. Nat'l. Cancer Inst., 1990, 82, 4-6.)Consequently, the targeting of pro-angiogenic pathways is a strategybeing widely pursued in order to provide new therapeutics in these areasof great, unmet medical need. The role of tyrosine kinases involved inangiogenesis and in the vascularization of solid tumors has drawninterest. Until recently most interest in this area has focused ongrowth factors such as vascular endothelial growth factor (VEGF) and itsreceptors termed vascular endothelial growth factor receptor(s) (VEGFR).VEGF, a polypeptide, is nitogenic for endothelial cells in vitro andstimulates angiogenic responses in vivo. VEGF has also been linked toinappropriate angiogenesis (Pinedo, H. M. et al. The Oncologist, Vol.5,No. 90001, 1-2, April 2000). VEGFR(s) are protein tyrosine kinases(PTKs). PTKs catalyze the phosphorylation of specific tyrosyl residuesin proteins involved in the regulation of cell growth anddifferentiation. (A. F. Wilks, Progress in Growth Factor Research, 1990,2, 97-111; S. A. Courtneidge, Dev. Supp. 1, 1993,57-64; J. A. Cooper,Sernin. Cell Biol., 1994, 5(6),377-387; R. F. Paulson, Semin. Immunol.,1995, 7(4),267-277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3),394-401).

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1);VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4): These receptors are involvedin angiogenesis and participate in signal transduction (Mustonen, T. etal. J. Cell Biol. 1995, 129: 895-898). Of particular interest isVEGFR-2, which is a transmembrane receptor PTK expressed primarily inendothelial cells. Activation of VEGFR-2 by VEGF is a critical step inthe signal transduction pathway that initiates tumor angiogenesis. VEGFexpression may be constitutive to tumor cells and can also beupregulated in response to certain stimuli. One such stimuli is hypoxia,where VEGF expression is upregulated in both tumor and associated hosttissues. The VEGF ligand activates VEGFR-2 by binding with itsextracellular VEGF binding site. This leads to receptor dimerization ofVEGFRs and autophosphorylation of tyrosine residues at the intracellularkinase domain of VEGFR-2. The kinase domain operates to transfer aphosphate from ATP to the tyrosine residues, thus providing bindingsites for signaling proteins downstream of VEGFR-2 leading ultimately toinitiation of angiogenesis (McMahon, G., The Oncologist, Vol.5, No.90001, 3-10, April 2000).

Angiopoietin 1 (Ang1), a ligand for the endothelium-specific receptortyrosine kinase TIE-2 is a novel angiogenic factor (Davis et al., Cell,1996, 87: 1161-1169; Partanen et al., Mol. Cell Biol., 12: 1698-1707(1992); U.S. Pat Nos. 5,521,073; 5,879,672; 5,877,020; and 6,030,831).The acronym TIE represents “tyrosine kinase containing Ig and EGFhomology domains”. TIE is used to identify a class of receptor tyrosinekinases, which are exclusively expressed in vascular endothelial cellsand early hemopoietic cells. Typically, TIE receptor kinases arecharacterized by the presence of an EGF-like domain and animmunoglobulin (IG) like domain, which consists of extracellular foldingunits, stabilized by intra-chain disulfide bonds (Partanen et al., Curr.Topics Microbiol. Immunol., 1999, 237: 159-172). Unlike VEGF, whichfunctions during the early stages of vascular development, Ang1 and itsreceptor TE-2 function in the later stages of vascular development,i.e., during vascular remodeling (remodeling refers to formation of avascular lumen) and maturation (Yancopoulos et al., Cell, 1998, 93:661-664; Peters, K. G., Circ. Res., 1998, 83(3): 342-3; Suri et al.,Cell 87, 1996: 1171-1180).

Consequently, inhibition of TIE-2 would be expected to serve to disruptremodeling and maturation of new vasculature initiated by angiogenesisthereby disrupting the angiogenic process. Furthermore, inhibition atthe kinase domain binding site of VEGFR-2 would block phosphorylation oftyrosine residues and serve to disrupt initiation of angiogenesis.Presumably then, inhibition of TIE-2 and/or VEGFR-2 should prevent tumorangiogenesis and serve to retard or eradicate tumor growth. Accordingly,a treatment for cancer or other disorder associated with inappropriateangiogenesis could be provided. Inhibitors of Raf kinases have beensuggested for use in disruption of tumor cell growth and hence in thetreatment of cancers, e.g., melanoma, histiocytic lymphoma, lungadenocarcinoma, colorectal, ovarian, and small cell lung cancer andpancreatic and breast carcinoma; (Helen Davies et al., Nature, 2002,417: 949. Activated cell surface receptors activate ras/rap proteins atthe inner aspect of the plasma-membrane which in turn recruit andactivate Raf proteins. Activated Raf proteins phosphorylate and activatethe intracellular protein kinases MEK1 and MEK2. In turn, activated MEKscatalyse phosphorylation and activation of p42/p44 mitogen-activatedprotein kinase (MAPK). A variety of cytoplasmic and nuclear substratesof activated MAPK are known which directly or indirectly contribute tothe cellular response to environmental change. Three distinct genes havebeen identified in mammals that encode Raf proteins; A-Raf, B-Raf andC-Raf (also known as Raf-1) and isoformic variants that result fromdifferential splicing of mRNA are known. Presumably then, inhibition ofRaf kinase should serve to retard or eradicate tumor growth.Accordingly, a treatment for cancer could be provided.

The pyridinyl-benzoheterocycyl compounds are inhibitors of one or moreof TIE-2 kinase activity, VEGFR-2 kinase activity, VEGFR-3 kinaseactivity or Raf kinase activity. Such pyridinyl-benzoheterocycylderivatives are useful in the treatment of disorders, mediated by atleast one of inappropriate TIE-2 kinase, VEGFR-2 kinase, VEGFR-3activity or Raf kinase activity (which may include cancer and/ordiseases afflicting mammals which is characterized by cellularproliferation in the area of disorders associated withneo-vascularization and/or vascular permeability), and/or disorderscharacterized by inappropriate angiogenesis; and/or for treating cancerand/or a disease afflicting afflicting mammals which is characterized bycellular proliferation in the area of disorders associated withneo-vascularization and/or vascular permeability.

SUMMARY OF THE INVENTION

This invention is directed to a compound of Formula I:

wherein:

n is an integer of 1,2, or 3;

R^(A) is —CONHR¹, —NHR¹, —NHCOR¹, —NHCONHR¹, —NHCO₂R¹, —NHSO₂R¹ or—NHSO₂NHR¹;

wherein R¹ is hydrogen or an optionally substituted C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl,heterocyclyl, aryl-C₁-C₄ allyl- or heteroaryl-C₁-C₄ alkyl- group,

where said optionally substituted R¹ group is optionally substitutedwith one or more substituents independently selected from halogen,—R^(1a), —OR^(1a), —SR^(1a), —SO₂R^(1c) —NR^(1a)R^(1b), cyano, nitro,—COR^(1c), —CO₂R^(1a), —NR^(1b)COR^(1a), —CONR^(1a)R^(1b),—NR^(1b)SO₂R^(1c), and —SO₂NR^(1a)R^(1b),

where R^(1a) is hydrogen or an optionally substituted C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl,heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇ cycloalkyl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄ alkenyl-,C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-, heteroaryl-C₂-C₄ alkenyl-,heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄ alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄alkynyl-, heteroaryl-C₂-C₄ alkynyl-, or heterocycyl-C₂-C₄ alkynyl-group,

R^(1b) is hydrogen or unsubstituted C₁-C₄ alkyl, and

R^(1c) is an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, aryl-C₁-C₄alkyl-, C₃-C₇ cycloalkyl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄ alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄alkenyl-, heteroaryl-C₂-C₄ alkenyl-, heterocycyl-C₂-C₄ alkenyl-,aryl-C₂C₄ alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkynyl-, heteroaryl-C₂-C₄alkynyl-, or heterocycyl-C₂-C₄ alkynyl- group,

where each optionally substituted R^(1a) group and R^(1c) group isindependently optionally substituted with one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl,—OC₁-C₄ haloalkyl, halogen, —OH, —NH₂, —N(C₁-C₄ alkyl(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), cyano, nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl,—CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ haloalkyl,—OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄ alkyl), and—NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ alkyl is unsubstituted C₁-C₄alkyl,

or R^(1a) and R^(1b), together with the nitrogen atom to which they areattached, form an optionally substituted heterocycyl or heteroaryl ringwhich optionally contains one or more additional heteroatom moietiesselected from O, S, SO, SO₂, N and N→O, wherein said optionallysubstituted heterocycyl or heteroaryl ring is optionally substitutedwith one or more substituents independently selected from C₁-C₄ alkyl,C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halogen, —OH, —NH₂,—N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), cyano, nitro, oxo,—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄alkyl), and —NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ alkyl isunsubstituted C₁-C₄alkyl,

X is NR², O, S, SO or SO₂,

wherein R² is hydrogen or an optionally substituted C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl,heterocyclyl, aryl-C₁-C₄ alkyl- or heteroaryl-C₁-C₄ alkyl- group,

where said optionally substituted R² group is optionally substitutedwith one or more substituents independently selected from halogen,—R^(2a), OR^(2a), —SR^(2a), —SO₂R^(2c) —NR^(2a)R^(2b), cyano, nitro,—COR^(2c), —CO₂R^(2a), —NR^(2b)COR^(2a), —CONR^(2a)R^(2b),—NR^(2b)SO₂R^(2c), and —SO₂NR^(2a)R^(2b),

where R^(2a) is hydrogen or an optionally substituted C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl,heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇ cycloalkyl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄ alkenyl-,C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-, heteroaryl-C₂-C₄ alkenyl-,heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄ alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄alkynyl-, heteroaryl-C₂-C₄ alkynyl-, or heterocycyl-C₂-C₄ alkynyl-group,

R^(2b) is hydrogen or unsubstituted C₁-C₄ alkyl, and

R^(2c) is an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, aryl-C₁-C₄alkyl-, C₃-C₇ cycloalkyl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄ alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄alkenyl-, heteroaryl-C₂-C₄ alkenyl-, heterocycyl-C₂-C₄ alkenyl-,aryl-C₂-C₄ alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkynyl-, heteroaryl-C₂-C₄alkynyl-, or heterocycyl-C₂-C₄ alkynyl- group,

where each optionally substituted R^(2a) group and R^(2c) group isindependently optionally substituted with one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl,—OC₁-C₄ haloalkyl, halogen, —OH, —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), cyano, nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl,—CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ haloalkyl,—OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄ alkyl), and—NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ alkyl is unsubstituted C₁-C₄alkyl,

or R^(2a) and R^(2b), together with the nitrogen atom to which they areattached, form an optionally substituted heterocycyl or heteroaryl ringwhich optionally contains one or more additional heteroatom moietiesselected from O, S, SO, SO₂, N and N→O, wherein said optionallysubstituted heterocycyl or heteroaryl ring is optionally substitutedwith one or more substituents independently selected from C₁-C₄ alkyl,C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halogen, —OH, —NH₂,—N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), cyano, nitro, oxo,—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄alkyl), and —NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ alkyl isunsubstituted C₁-C₄ alkyl,

R^(B) is —CONHR³, —SO₂R³; —CO₂R³, —COC(R⁴R⁵)R³,

wherein R³ is hydrogen or an optionally substituted C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, C₃₋C₇ cycloalkyl, heteroaryl,heterocyclyl, aryl-C₁-C₄ alkyl- or heteroaryl-C₁-C₄ alkyl- group,

where said optionally substituted R³ group is optionally substitutedwith one or more substituents independently selected from halogen,—R^(3a), —OR^(3a), —SR^(3a), —SO₂R^(3c) —NR^(3a)R^(3b), cyano, nitro,—COR^(3c), —CO₂R^(3a), —NR^(3b)COR^(3a), —CONR^(3a)R^(3b),—NR^(3b)SO₂R^(3c), and —SO₂NR^(3a)R^(3b),

where R3a is hydrogen or an optionally substituted C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl,heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇ cycloalkyl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄ alkenyl-,C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-, heteroaryl-C₂-C₄ alkenyl-,heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄ alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄alkynyl-, heteroaryl-C₂-C₄ alkynyl-, or heterocycyl-C₂-C₄ alkynyl-group,

R^(3b) is hydrogen or unsubstituted C₁-C₄ alkyl, and

R^(3c) is an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, aryl-C₁-C₄alkyl-, C₃-C₇ cycloalkyl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄ alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄alkenyl-, heteroaryl-C₂-C₄ alkenyl-, heterocycyl-C₂-C₄ alkenyl-,aryl-C₂-C₄ alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkynyl-, heteroaryl-C₂-C₄alkynyl-, or heterocycyl-C₂-C₄ alkynyl- group,

where each optionally substituted R^(3a) group and R^(3c) group isindependently optionally substituted with one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl,—OC₁-C₄ haloalkyl, halogen, —OH, —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), cyano, nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl,—CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ haloalkyl,—OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄ alkyl), and—NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ alkyl is unsubstituted C₁-C₄alkyl,

or R^(3a) and R^(3b), together with the nitrogen atom to which they areattached, form an optionally substituted heterocycyl or heteroaryl ringwhich optionally contains one or more additional heteroatom moietiesselected from O, S, SO, SO₂, N and N→O, wherein said optionallysubstituted heterocycyl or heteroaryl ring is optionally substitutedwith one or more substituents independently selected from C₁-C₄ alkyl,C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halogen, —OH, —NH₂,—N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), cyano, nitro, oxo,—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄alkyl), and —NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ allyl isunsubstituted C₁-C₄ alkyl, and

R⁴ and R⁵ are independently selected from hydrogen and unsubstitutedC₁-C₄ alkyl,

or R⁴ and R⁵, taken together with the carbon atom to which they areattached, represent an optionally substituted 3-6membered saturatedcarbocyclic ring, where said optionally substituted 3-6membered ring issubstituted with one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halogen,—OH, —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), cyano, nitro,oxo, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl,—SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—NHS(O)₂(C₁-C₄ alkyl), and —NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄alkyl is unsubstituted C₁-C₄ alkyl,

or a salt, solvate, or physiologically functional derivative thereof.

This invention is also directed to a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of FormulaI, or a salt, solvate, or a physiologically functional derivativethereof and one or more of pharmaceutically acceptable carriers,diluents and excipients. In another embodiment, this invention isdirected to a method of treating a disorder in a mammal, said disorderbeing mediated by at least one of inappropriate TIE-2, VEGFR-2 VEGFR-3and Raf kinase activity, comprising: administering to said mammal atherapeutically effective amount of a compound of Formula I or a salt,solvate or a physiologically functional derivative thereof. In yetanother embodiment, this invention is directed to a compound of FormulaI, or a salt, solvate, or a physiologically functional derivativethereof for use in therapy. In another embodiment, this invention isdirected to the use of a compound of Formula I, or a salt, solvate, or aphysiologically functional derivative thereof in the preparation of amedicament for use in the treatment of a disorder mediated by at leastone of inappropriate TIE-2, VEGFR-2, VEGFR-3 or Raf kinase activity. Ina further aspect of this invention, there is provided a method oftreating a disorder in a mammal, said disorder being mediated by atleast one of inappropriate TIE-2, VEGFR-2, VEGFR-3 and Raf kinaseactivity, comprising: administering to said mammal therapeuticallyeffective amounts of (i) a compound of Formula I, or a salt, solvate orphysiologically functional derivative thereof and (ii) an agent toinhibit growth factor receptor function. This invention is also directedto a method of treating a disorder in a mammal, said disorder beingcharacterized by inappropriate angiogenesis, comprising: administeringto said mammal a therapeutically effective amount of a compound ofFormula I, or a salt, solvate or physiologically functional derivativethereof.

DETAILED DESCRIPTION OF THE INVENTION

All documents cited or referred to herein, including issued patents,published and unpublished patent applications, and other publicationsare hereby incorporated herein by reference as though fully set forth.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “alkyl” refers to a straight or branched chainsaturated hydrocarbon radical having from one to twelve carbon atoms,unless otherwise specified, optionally substituted with one or moresubstituents as defined herein. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like. The term“C₁-C₆ alkyl” refers to an alkyl group as defined above containing atleast 1, and at most 6, carbon atoms. Examples of branched or straightchained “C₁-C₆ alkyl” groups useful in the present invention include,but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl,n-butyl, t-butyl, n-pentyl, and isopentyl.

As used herein, the term “alkenyl” refers to a straight or branchedchain hydrocarbon radical having from two to ten carbons, unlessotherwise specified, and at least one carbon-carbon double bond,optionally substituted with one or more substituents as defined herein.Examples of “alkenyl” as used herein include ethenyl, propenyl,1-butenyl, 2-butenyl, and isobutenyl. The term “C₂-C₆ alkenyl” refers toan alkenyl group as defined above containing at least 2, and at most 6,carbon atoms. Examples of “C₂-C₆ alkenyl” groups useful in the presentinvention include, but are not limited to, ethenyl, propenyl, 1-butenyl,2-butenyl, and isobutenyl.

“Alkynyl” refers to a straight or branched chain hydrocarbon radicalhaving from two to ten carbons, unless otherwise specified, and at leastone carbon-carbon triple bond, optionally substituted with one or moresubstituents as defined herein. Examples of “alkynyl” as used herein,include but are not limited to acetylenyl, 1-propynyl, 1-butynyl,2-butynyl, 1-pentynyl, and 1-hexynyl.

The term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br),or iodine (I) and the term “halo” refers to the halogen radicals fluoro,chloro, bromo, and iodo.

As used herein, the term “C₁-C₆ haloalkyl” refers to an alkyl group asdefined above containing at least 1, and at most 6, carbon atomssubstituted with at least one halo group, halo being as defined herein.Examples of branched or straight chained “C]-C₆ haloalkyl” groups usefulin the present invention include, but are not limited to, methyl, ethyl,propyl, isopropyl, isobutyl and n-butyl substituted independently withone or more halos, e.g., fluoro, chloro, bromo and iodo, e.g.,trifluoromethyl.

As used herein, the term “C₃-C₇ cycloalkyl” refers to a non-aromaticcyclic hydrocarbon radical having from three to seven carbon atoms whichmay be saturated or partially unsaturated and which is optionallysubstituted with one or more substituents as defined herein. Exemplary“C₃-C₇ cycloalkyl” groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl andcycloheptyl.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring fused to oneor more optionally substituted benzene rings to form a ring system,which rings are optionally substituted with one or more substituents asdefined herein. Such a ring or ring system may be optionally fused toone or more optionally substituted aryl rings (including benzene rings)or cycloalkyl rings. Examples of “aryl” groups include, but are notlimited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and indenyl,as well as substituted derivatives thereof.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered ring containing one or moreheteroatornic ring moieties selected from S, SO, SO₂, O , N, or N-oxide,optionally substituted with one or more substituents as defined herein.Such a ring can be saturated or have one or more degrees of saturation.Such a ring may be optionally fused to one or more other optionallysubstituted, “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of“heterocyclic” moieties include, but are not limited to,tetrahydrofuranyl, pyranyl, 1,4-dioxyl, 1,3-dioxyl, piperidinyl,pyrrolidinyl, morpholinyl, tetrahydrothiopyranyl, tetrahydrotbienyl, andthe like.

As used herein, the term “heteroaryl” refers to an optionallysubstituted monocyclic five to seven membered aromatic ring containingone or more heteroatomic ring moieties selected from S, SO, SO₂, O, N,or N-oxide, or to such an aromatic ring fused to one or more, optionallysubstituted, heteroaryl rings, aryl rings (including benzene rings),heterocyclic rings, or cycloalkyl rings (e.g., a bicyclic or tricyclicring system), which rings are optionally substituted with one or moresubstituents as defined herein. Examples of “heteroaryl” groups usedherein include, but are not limited to, furanyl, thiophenyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl,pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl, dihydrobenzothienyl, indolyl, indazolyl, andsubstituted versions thereof.

When the term “alkyl” (or alkenyl or alkynyl) is used in combinationwith other substituent groups, such as “haloalkyl,” “aryl-C₁-C₄ alkyl-,”“aryl-C₂-C₄ alkenyl-,” or “heteroaryl-C₁-C₄ alkyl-”, the term “alkyl”(or alkenyl or alkynyl) is intended to encompass a divalent straight orbranched-chain hydrocarbon radical. For example, “cycloalkylalkyl” isintended to mean the radical -alkyl-cycloalkyl, wherein the alkyl moietythereof is a divalent straight or branched-chain saturated hydrocarbonradical and the cycloalkyl moiety thereof is as defined herein, and isrepresented by the bonding arrangement present in the groups—CH₂-cyclopropyl, —CH₂-Cyclohexyl, or —CH₂(CH₃)CHCH₂-cyclopentenyl.Examples of “aryl-C₁-C₄ alkyl-” include, but are not limited to, benzyland phenylpropyl. Examples of “heteroaryl-C₁-C₄ alkyl-” include, but arenot limited to, 2-pyridylmethyl, 3-isoxazolylmethyl,3-(1-methyl-5-t-butyl-pyrazoyl)methyl, 3-isoxazolylmethyl, and2-imidazolyl ethyl. Examples of “heterocycyl-C₁-C₄ alkyl-” include, butare not limited to, 1-methyl-piperidinylpropyl, morpholinoethyl,morpholinopropyl, pyrrolidinonyl-butyl, pyrrolidinyl-butyl, andpyrrolidinyl-pentyl. The term “aryl-C₂-C₄ alkenyl-” is intended to meanthe radical -alkenyl-aryl, wherein the alkenyl moiety thereof is adivalent straight or branched-chain hydrocarbon radical containing twoto four carbon atoms and at least one carbon-carbon double bond and thearyl moiety thereof is as defined herein, and is represented by thebonding arrangement present in a styryl group, e.g., —CH═CH-phenyl.

It will be understood that when a group or moiety is “optionallysubstituted,” the group or moiety may be unsubstituted or may besubstituted by one or more of the substituents defined herein, whereeach substituent is selected independently.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a manual is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear:to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula I or a salt or physiologically functional derivative thereof)and a solvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include, but are not limited to, water, methanol,ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include, without limitation, water,ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain of the compounds described herein contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers. Thecompounds of this invention include mixtures of enantiomers as well aspurified enantiomers or enantiomerically enriched mixtures. Alsoincluded within the scope of the invention are the individual isomers ofthe compounds represented by Formula I above as well as any wholly orpartially equilibrated mixtures thereof. The present invention alsocovers the individual isomers of the compounds represented by theformulas above as mixtures with isomers thereof in which one or morechiral centers are inverted. Also, it is understood that all tautomersand mixtures of tautomers of the compounds of Formula I are includedwithin the scope of the compounds of Formula I.

In one particular embodiment of the present invention are compoundshaving Formula I wherein n is 1 or 2. In another particular embodimentof the invention are compounds of Formula I wherein n is 1. In anotherembodiment of the invention are compounds of Formula I wherein X is O orNR². In yet another embodiment of the invention are compounds of FormulaI wherein X is O.

Another embodiment of the compounds of Formula I are compounds ofFormula II:

More specific embodiments of the compounds of Formula I are compounds ofFormula III

In one embodiment of the invention, R^(A) is —CONHR¹, —NHCOR¹, or—NHSO₂R¹, where R¹ is C₁-C₆ alkyl, aryl, heteroaryl, heterocycyl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄ alkyl-,wherein said C₁-C₆ alkyl is optionally substituted with one ore moresubstituents independently selected from —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄alkyl), and —NH(C₁-C₄ alkyl), or said aryl, heteroaryl or heterocycyl orthe aryl, heteroaryl or heterocycyl moiety of said aryl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄ alkyl- is unsubstituted orsubstituted by one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl and halogen.

In a another embodiment of the invention, R^(A) is —-CONHR¹. In afurther embodiment of the invention, R^(A) is -CONHR¹ and R¹ is C₁-C₆alkyl, aryl, heteroaryl, heterocycyl, aryl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄ alkyl-, wherein said C₁-C₆alkyl is optionally substituted with one ore more substituentsindependently selected from —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), and—NH(C₁-C₄ alkyl), or said aryl, heteroaryl or heterocycyl or the aryl,heteroaryl or heterocycyl moiety of said aryl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄ alkyl- is unsubstituted orsubstituted by one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl and halogen. In yet a further embodiment ofthe invention, R^(A) is —CONHR¹ and R¹ is methyl, ethyl, phenyl, benzyl,phenethyl, N,N diethylaminopropyl, N-methyl-piperidinyl,piperidinyl-ethyl, pyrrolidinyl-butyl, morpholino-ethyl, ormorpholino-propyl.

In another embodiment of the invention, R^(B) is —CONHR³, —SO₂R³, or—COC(R⁴R⁵)R³ where R³ is aryl or heteroaryl, wherein said aryl orheteroaryl is unsubstituted or substituted by one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen, C₁-C₆allyl, C₃-C₆ cycloalkyl, aryl, heteroaryl and heterocycyl.

In yet another embodiment of the invention, R^(B) is —CONHR³ or —SO₂R³where R³ is aryl or heteroaryl, wherein said aryl or heteroaryl isunsubstituted or substituted by one or more substituents independentlyselected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, heteroaryl and heterocycyl.

In a yet another embodiment of the invention, R^(B) is —CONHR and R³ isaryl or heteroaryl, wherein said aryl or heteroaryl is unsubstituted orsubstituted by one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,aryl, heteroaryl and heterocycyl.

In a yet another embodiment of the invention, R^(B) is —CONHR³ and R³ issubstituted phenyl or substituted isoxazolyl, where said phenyl orisoxazolyl is substituted by one or more substituents independentlyselected from F, Cl, CF₃, or tert-butyl.

It is to be understood that reference to compounds of Formula I, II orIII, herein refers to all compounds within the scope of Formula I, II orIII, as defined above with respect to n, X, R, R^(B), R¹, R² and R³,unless specifically limited otherwise.

For example one embodiment of this invention is directed to a compoundof Formula I wherein: n is 1; R^(A) is —CONHR¹, —NHCOR¹, —NHSO₂R¹, whereR¹ is C₁-C₆ alkyl, aryl, heteroaryl, heterocycyl, aryl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄ alkyl-, wherein said C₁-C₆alkyl is optionally substituted with one ore more substituentsindependently selected from —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), and—NH(C₁-C₄ alkyl), or said aryl, heteroaryl or heterocycyl or the aryl,heteroaryl or heterocycyl moiety of said aryl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄ alkyl- is unsubstituted orsubstituted by one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl and halogen; X is O; and R^(B) is —CONHR³or —SO₂NHR³; where R³ is aryl or heteroaryl, wherein said aryl orheteroaryl is unsubstituted or substituted by one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl or halogen; ora salt, solvate, or physiologically functional derivative thereof.

In another embodiment of the compounds of Formula I, n is 1;R^(A) is—CONHR¹, and R¹ is methyl, ethyl, phenyl, benzyl, phenethyl, N,Ndiethylaminopropyl, N-methyl-piperidinyl, piperidinyl-ethyl,pyrrolidinyl-butyl, morpholino-ethyl, or morpholino-propyl; X is O; andR^(B) is —CONHR³, where R³ is substituted phenyl or substitutedisoxazolyl, where said phenyl or isoxazolyl is substituted by one ormore substituents independently selected from F, Cl, CF₃, or tert-butyl;or a salt, solvate, or physiologically functional derivative thereof.

Specific examples of compounds of the present invention include thefollowing compounds:

5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-l-carboxylicacid (4′-chloro-3′-tritluoromethyl-phenyl)-amide,

5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (2′-fluoro-5′-trifluoromethyl-phenyl)-amide,

5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (2′-fluoro-5′-trifluoromethyl-phenyl)-amide,

5-(2-hexylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide trifluoroacetate,

5-2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (4′-fluoro-3′-trifluoromethyl-phenyl)-amide,

5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3′-chlorophenyl)-amide,

5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (bis-3′,5′-trifluoromethylphenyl)-amide,

5-(2-ethylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide,

5-(2-propylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide,

5-(2-phenylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide,

5-(2-benzylcarbamoyl-pyridin-4-yloxy-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide,

5-(2-phenethylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide,

5-[2-(1-methyl-piperidin-4-ylcarbamoyl)-pyridinyloxy]-2,3-hydro-indole-1-carboxylicacid(3-trifuoromethyl-phenyl)-amide,

5-[2-(1-methyl-piperidin-4-ylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid(3-trifuoromethyl-phenyl)-amide,

5-[2-(3-diethylamino-propylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide,

5-[2-(3-morpholin-4-propylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide,

5-[2-(2-piperidin-1-yl-ethylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide,

5-[2-(4-pyrrolidin-1-yl-butylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)amide,

5-2-isopropylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide trifluoroacetate,

5-2-isopropylcarbamoyl-pyridin-4-yloxy)-2,3-dihydroindole-1-carboxylicacid (3-trifuoromethyl-phenyl)-amide trifluoroacetate,

5-[2-(2-methoxy-ethylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide trifluoroacetate,

5-[2-(2-phenoxy-ethylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide trifluoroacetate,

5-[2-(3-ethoxy-propylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide trifluoroacetate,

5-[2-(3-isopropoxy-propylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide trifluoroacetate, and

5-(2-hexylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amide trirluoroacetate,

or a salt, solvate, or physiologically functional derivative thereof.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt” isintended to describe a salt that retains the biological effectiveness ofthe free acid or base of a specified compound and is not biologically orotherwise undesirable.

If an inventive compound is a base, a desired salt may be prepared byany suitable method known in the art, including treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like, or withan organic acid, such as acetic acid, trifluoroacetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such asglucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citricacid or tartaric acid, amino acid, such as aspartic acid or glutamicacid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonicacid, such as p-toluenesulfonic acid, methanesulfonic acid,ethanesulfonic acid or the like. Examples of pharmaceutically acceptablesalts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,phosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates,phenylpropionates, phenylbutrates, citrates, lactates,γ-hydroxybutyrates, glycollates, tartrates mandelates, and sulfonates,such as xylenesulfonates, methanesulfonates, propanesulfonates,naphthalene-1-sulfonates and naphthalene-2-sulfonates.

If an inventive compound is an acid, a desired salt may be prepared byany suitable method known to the art, including treatment of the freeacid with an inorganic or organic base, such as an amine (primary,secondary, or tertiary), an alkali metal or alkaline earth metalhydroxide, or the like. Illustrative examples of suitable salts includeorganic salts derived from amino acids such as glycine and arginine,ammonia, primary, secondary, and tertiary amines, and cyclic amines,such as ethylene diamine, dicyclohexylamine, ethanolamine, piperidine,morpholine, and piperazine, as well as inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum, and lithium.

Other salts, which are not pharmaceutically acceptable, may be useful inthe preparation of compounds of this invention and these form a furtheraspect of the invention.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of Formula I, II or III, as well as salts,solvates and physiological functional derivatives thereof, may beadministered as the raw chemical, it is possible to present the activeingredient as a pharmaceutical composition. Accordingly, the inventionfurther provides pharmaceutical compositions, which includetherapeutically effective amounts of compounds of the Formula I, II orIII and/or salts, solvates and/or physiological functional derivativesthereof, and one or more pharmaceutically acceptable carriers, diluents,or excipients. The compounds of the Formula I, II or III and salts,solvates and physiological functional derivatives thereof, are asdescribed above. The carrier(s), diluent(s) or excipient(s) must beacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof inaccordance with another aspect of the invention there is also provided aprocess for the preparation of a pharmaceutical formulation includingadmixing a compound of the Formula I, II or III, or salts, solvates andphysiological functional derivatives thereof, with one or morepharmaceutically acceptable carriers, diluents or excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the Formula I,II or III, depending on the condition being treated, the route ofadministration and the age, weight and condition of the patient, orpharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Preferred unit dosage formulations are those containing a daily dose orsub-dose, as herein recited, or an appropriate fraction thereof, of anactive ingredient. Furthermore, such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

For example, pharmaceutical formulations adapted for oral administrationmay be presented as discrete units such as capsules or tablets; powdersor granules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffm, a resorption accelerator such as a quaternary salt and/or anabsorption agent such as bentonite, kaolin or dicalcium phosphate. Thepowder mixture can be granulated by wetting with a binder such as syrup,starch paste, acadia mucilage or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticling to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating comprising a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of Formula I, II or III, and salts, solvates andphysiological functional derivatives thereof, can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

The compounds of Formula I, I or III and salts, solvates andphysiological functional derivatives thereof may also be delivered bythe use of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide—phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 1986,3(6):318.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior.;to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of Formula I, II or III for the treatment of neoplastic growth,for example colon or breast carcinoma, will generally be in the range of0.1 to 100 mg/kg body weight of recipient (mammal) per day and moreusually in the range of 1 to 10 mg/kg body weight per day. Thus, for a70kg adult mammal, the actual amount per day would usually be from 70 to700 mg and this amount may be given in a single dose per day or moreusually in a number (such as two, three, four, five or six) of sub-dosesper day such that the total daily dose is the same. An effective amountof a salt or solvate, or physiologically functional derivative thereof,may be determined as a proportion of the effective amount of thecompound of Formula I, II or III per se. It is envisaged that similardosages would be appropriate for treatment of the other conditionsreferred to herein.

The compounds of the present invention and their salts and solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in anti-cancer therapy,combination with other chemotherapeutic, hormonal or antibody agents isenvisaged as well as combination with surgical therapy and radiotherapy.Combination therapies according to the present invention thus comprisethe administration of at least one compound of Formula I, II or III or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof, and the use of at leastone other cancer treatment method. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of Formula I, II or III or a pharmaceuticallyacceptable salt or solvate thereof, or a physiologically functionalderivative thereof, and at least one other pharmaceutically activeagent, preferably an anti-neoplastic agent. The compound(s) of FormulaI, II or III and the other pharmaceutically active agent(s) may beadministered together or separately and, when administered separatelythis may occur simultaneously or sequentially in any order. The amountsof the compound(s) of Formula L II or m and the other pharmaceuticallyactive agent(s) and the relative timings of administration will beselected in order to achieve the desired combined therapeutic effect.

The compounds of the Formula I, II or III or salts, solvates, orphysiologically functional derivatives thereof and at least oneadditional cancer treatment therapy may be employed in combinationconcomitantly or sequentially in any therapeutically appropriatecombination with such other anti-cancer therapies. In one embodiment,the other anti-cancer therapy is at least one additionalchemotherapeutic therapy including administration of at least oneanti-neoplastic agent. The administration in combination of a compoundof Formula I, II or III or salts, solvates, or physiologicallyfunctional derivatives thereof with other anti-neoplastic agents may bein combination in accordance with the invention by administrationconcomitantly in (1) a unitary pharmaceutical composition including bothcompounds or (2) separate pharmaceutical compositions each including oneof the compounds. Alternatively, the combination may be administeredseparately in a sequential manner wherein one anti-neoplastic agent isadministered first and the other second or vice versa. Such sequentialadministration may be close in time or remote in time.

Anti-neoplastic agents may induce anti-neoplastic effects in acell-cycle specific manner, i.e., are phase specific and act at aspecific phase of the cell cycle, or bind DNA and act in a noncell-cycle specific manner, i.e., are non-cell cycle specific andoperate by other mechanisms.

Anti-neoplastic agents useful in combination with the compounds andsalts, solvates or physiologically functional derivatives thereof ofFormula I, II or III include the following:

(1) cell cycle specific anti-neoplastic agents include, but are notlimited to, diterpenoids such as paclitaxel and its analog docetaxel;vinca alkaloids such as vinblastine, vincristine, vindesine, andvinorelbine; epipodophyllotoxins such as etoposide and teniposide;fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine;antimetabolites such as gemciabine, Fludarabine, methotrexate,cladrabine, cytarabine, mercaptopurine and thioguanine; andcamptothecins such as 9-amino camptothecin, irinotecan, topotecan, andthe various-optical forms of7-(4methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;.

(2) cytotoxic chemotherapeutic agents including, but not limited to,alkylating agents such as melphalan, chlorambucil, cyclophosphamide,mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine,and dacarbazine; anti-tumor antibiotics such as beomycin, doxonibicin,daunomycin, epirubicin, idarubicin, mitoxantrone, mitomycin-C,dacttinomycin and mithramycin; and platinum coordination complexes suchas cisplatin, carboplatin, and oxaliplatin; and

(3) other chemotherapeutic agents including, but not limited to,anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifeneand iodoxyfene; progestrogens such as megestrol acetate; aromataseinhibitors such as anastrozole, letrazole, vorazole, and exemestane;antiandrogens such as flutamide, nilutamnide, bicalutamide, andcyproterone acetate; glucocorticoids such as prednisone and decadron;LHRH agonists and antagonists such as goserelin acetate and luprolide;testosterone 5α-dihydroreductase inhibitors such as dutasteride,finasteride; metalloproteinase inhibitors such as marimastat;antiprogestogens; other biologic agents such as L-asparaginase;urokinase plasminogen activator receptor function inhibitors; smallmolecule and antibody growth factor function inhibitors such asinhibitors of the functions of hepatocyte growth factor; erb-B2, erb-B4,epidermal growth factor receptor (EGFR), platelet derived growth factorreceptor (PDGFR), tyrosone kinases such as, EphB₄, c-kit and bcr/abl),vascular endothelial growth factor receptor (VEGFR), and TIE-2 (otherthan those VEGFR and TIE-2 inhibitors described in the presentinvention); and other kinase inhibitors such as inhibitors of CDK2 andCDK4; and other antitumor agents such as thalidomide, immunoconjugates,cytokines, such as IL-2, IFN alpha and beta, tumor vaccines includingdendritic cell vaccines, all cyclooxygenase inhibitors and radiationsensitizers such as temazolamide

The compounds of Formula I, II or III and salts, solvates andphysiological functional derivatives thereof, are active as inhibitorsof at least one of the protein kinases TIE-2, VEGFR-2, VEGFR-3 and Raf.

The present invention thus also provides compounds of Formula I, I orIII and pharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders mediated by atleast one of inappropriate TIE-2, VEGFR-2, VEGFR-3 and Raf kinaseactivity.

The inappropriate TIE-2, VEGFR-2, VEGFR-3 and/or Raf kinase activityreferred to herein is any TIE-2, VEGFR-2, VEGFR-3 and/or Raf kinaseactivity that deviates from the normal TIE-2, VEGFR-2, VEGFR-3 and/orRaf kinase activity expected in a particular mammalian subject.Inappropriate TIE-2, VEGFR-2, VEGFR-3 and/or Raf kinase activity maytake the form of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of TIE-2, VEGFR-2, VEGFR-3and/or Raf kinase activity. Such inappropriate activity may result then,for example, from overexpression or mutation of the protein kinaseleading to inappropriate or uncontrolled activation. Furthermore, it isalso understood that unwanted TIE-2, VEGFR-2, VEGFR-3 kinase and/or Rafactivity may reside in an abnormal source, such as a malignancy. Thatis, the level of TIE-2, VEGFR-2, VEGFR-3 and/or Raf kinase activity doesnot have to be abnormal to be considered inappropriate, rather theactivity derives from an abnormal source.

In a like manner, the inappropriate angiogenesis referred to herein isany angiogenic activity that deviates from the normal angiogenicactivity expected in a particular mammalian subject. Inappropriateangiogenesis may take the form of, for instance, an abnormal increase inactivity, or an aberration in the timing and or control of angiogenicactivity. Such inappropriate activity may result then, for example, fromoverexpression or mutation of a protein kinase leading to inappropriateor uncontrolled activation. Furthermore, it is also understood thatunwanted angiogenic activity may reside in an abnormal source, such as amalignancy. That is, the level of angiogenic activity does not have tobe abnormal to be considered inappropriate, rather the activity derivesfrom an abnormal source.

The present invention is directed to methods of regulating, modulating,or inhibiting TIE-2, VEGFR-2, VEGFR-3 and/or Raf kinase for theprevention and/or treatment of disorders related to inappropriate TIE-2,VEGFR-2, VEGFR-3 and/or Raf activity.

In particular, the compounds of the present invention are useful in thetreatment of susceptible forms of cancer, including tumor growth andmetastasis. Furthermore, the compounds of the present invention can beused to provide additive or synergistic effects with certain existingcancer chemotherapies, and/or be used to restore effectiveness ofcertain existing cancer chemotherapies and radiation.

The compounds of the present invention may be also useful in thetreatment of one or more diseases afflicting mammals which arecharacterized by cellular proliferation in the area of disordersassociated with neo-vascularization and/or vascular permeabilityincluding blood vessel proliferative disorders including arthritis andrestenosis; fibrotic disorders including hepatic cirrhosis: andatherosclerosis; mesangial cell proliferative disorders includingglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombotic microangiopathy syndromes, organ transplant rejection andglomerulopathies; and metabolic disorders including psoriasis, diabetesmellitus, chronic wound healing, inflammatory diseases (e.g., rheumatoidarthritis), stroke and neurodegenerative diseases; also diabeticretinopathy; macular degeneration; other diseases characterized byocular neovascularization; and diseases characterized by hemangiomas.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by at least one ofinappropriate TIE-2, VEGFR-2, VEGFR-3 and Raf activity, which includesadministering to said subject an effective amount of a compound ofFormula I, II or III or a pharmaceutically acceptable salt, solvate, ora physiologically functional derivative thereof. In a preferredembodiment, the disorder is cancer, e.g., malignant tumors. Anotheraspect of the invention also provides such a method wherein the disorderis a disease afflicting mammals which are characterized by cellularproliferation in the area of disorders associated withneo-vascularization and/or vascular permeability, including thosedisclosed herein.

A further aspect of the invention provides a method of treatment of amammal suffering from cancer which includes administering to saidsubject an effective amount of a compound of Formula I, II or III or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof.

A further aspect of the present invention provides the use of a compoundof Formula I, II or III, or a pharmaceutically acceptable salt orsolvate thereof, or a physiologically functional derivative thereof, inthe preparation of a medicament for the treatment of a disordercharacterized by at least one of inappropriate TIE-2, VEGFR-2 VEGFR-3and Raf kinase activity. In a preferred embodiment, the disorder iscancer, e.g., malignant tumors. Another aspect of the invention alsoprovides such a use wherein the disorder is a disease afflicting mammalswhich are characterized by cellular proliferation in the area ofdisorders associated with neo-vascularization and/or vascularpermeability, including those disclosed herein.

A further aspect of the present invention provides the use of a compoundof Formula I, II or III, or a pharmaceutically acceptable salt orsolvate thereof, or a physiologically functional derivative thereof, inthe preparation of a medicament for the treatment of cancer,-e.g.,malignant tumors.

The mammal requiring treatment with a compound of the present inventionis typically a human being.

In another embodiment, therapeutically effective amounts of (a) thecompounds of Formula I, II or m or salts, solvates or physiologicallyderived derivatives thereof and (b) agents which inhibit kinasesignaling may be administered in combination to a mammal for treatmentof a disorder mediated by at least one of inappropriate TIE2, VEGFR-2,VEGFR-3 and Raf kinase activity, for instance in the treatment ofcancer, e.g., malignant tumors. Such kinase signaling receptors include,for example, EGFR, PDGFR, erbB2, erbB4, VEGFR, TIE-2, Raf, Akt, PI₃K,and mTor. Oncogenic kinase signaling receptors and agents that inhibittheir kinase function are described, for instance, in Kath, John C.,Exp. Opin. Ther. Patenzts (2000) 10(6): 803-818 and in Blume-Jensen,Peter, Nature (2001)411:355.

The compounds of the Formula I, II or III or salts, solvates, orphysiologically functional derivatives thereof and the agent forinhibiting growth factor receptor function may be employed incombination concomitantly or sequentially in any therapeuticallyappropriate combination. The combination may be employed in combinationin accordance with the invention by administration concomitantly in (1)a unitary pharmaceutical composition including both compounds, or (2)separate pharmaceutical compositions each including one of thecompounds. Alternatively, the combination may be administered separatelyin a sequential manner wherein one is administered first and the othersecond or vice versa. Such sequential administration may be close intime or remote in time.

In another aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate angiogenesis, including: administering to said mammal atherapeutically effective amount of a compound of Formula I II or III ora salt, solvate or physiologically functional derivative thereof. In oneembodiment, the inappropriate angiogenic activity is due to at least oneof inappropriate VEGFR1, VEGFR2, VEGFR3, or TIE-2 activity. In anotherembodiment, the inappropriate angiogenesis is due to at least one ofinappropriate VEGFR-2, VEGFR-3, and TIE-2 Kinase activity. In apreferred embodiment, the inappropriate angiogenic activity is due to atleast one of inappropriate VEGFR-2 and TIE-2 kinase activity. In afurther embodiment, the method further includes administering atherapeutically effective amount of a VEGFR2 inhibitor along with thecompounds of Formula 1, I[ or m or salts, solvates or physiologicallyfunctional derivatives thereof. Preferably the disorder is cancer; e.g.,malignant tumors. This aspect of the invention also provides suchmethods wherein the disorder is a disease afflicting mammals which arecharacterized by cellular proliferation in the area of disordersassociated with neo-vascularization and/or vascular permeability,including those disclosed herein.

In another aspect of the present invention, there is provided the use ofa compound of Formula I, I or m, or a salt, solvate or physiologicallyfunctional derivative thereof in the preparation of a medicament for usein treating a disorder in a mammal, said disorder being characterized byinappropriate angiogenesis. In one embodiment, the inappropriateangiogenic activity is due to at least one of inappropriate VEGFR1,VEGFR2, VEGFR3 or TIE-2 activity. In another embodiment, theinappropriate angiogenesis is due to at least one of inappropriateVEGFR-2, VEGFR-3, and TIE-2 kinase activity. In a preferred embodiment,the inappropriate angiogenic activity is due to at least one ofinappropriate VEGFR-2 and TIE-2 Kinase activity. In a furtherembodiment, the use further includes use of a VEGFR2 inhibitor toprepare said medicament. Preferably the disorder is cancer, e.g.,malignant tumors. This aspect of the invention also provides such useswherein the disorder is a disease afflicting mammals which arecharacterized by cellular proliferation in the area of disordersassociated with neo-vascularization and/or vascular permeability,including those disclosed herein. The combination of a compound ofFormula I, II or III or salts, solvates, or physiologically functionalderivatives thereof with a VEGFR2 inhibitor may be employed incombination in accordance with the invention by administrationconcomitantly in (1) a unitary pharmaceutical composition including bothcompounds, or (2) separate pharmaceutical compositions each includingone of the compounds. Alternatively, the combination may be administeredseparately in a sequential manier wherein one is administered first andthe other second or vice versa. Such sequential administration may beclose in time or remote in time.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by mediated by inappropriateRaf kinase activity, which includes administering to said subject aneffective amount of a compound of Formula I, II or III or apharmaceutically acceptable salt, solvate, or a physiologicallyfunctional derivative thereof. Raf protein kinases are key components ofsignal transduction pathways by which specific extracellular stimulielicit precise cellular responses in mammalian cells Activated cellsurface receptors activate ras/rap proteins at the inner aspect of theplasma membrane which in turn recruit and activate Raf proteins.Activated Raf proteins phosphorylate and activate the intracellularprotein kinases MEK1 and MEK2. In turn, activated MEKs catalysephosphorylation and activation of p42/p44 mitogen-activated proteinkinase (MAPK). A variety of cytoplasmic and nuclear substrates ofactivated MAPK are known which directly or indirectly contribute to thecellular response to environmental change. Three distinct genes havebeen identified in mammals that encode Raf proteins; A-Raf, B-Raf andC-Raf (also known as Raf-1) and isoformic variants that result fromdifferential splicing of mRNA are known.

Inhibitors of Raf kinases have been suggested for use in disruption oftumor cell growth and hence in the treatment of cancers, e.g., melanoma,histiocytic lymphoma, lung adenocarcinoma, colorectal, ovarian, andsmall cell lung cancer and pancreatic and breast carcinoma;

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the Examples.

Compounds of general Formula I, II or III may be prepared by methodsknown in the art of organic synthesis as set forth in part by thefollowing synthesis schemes. In all of the schemes described below, itis well understood that protecting groups for sensitive or reactivegroups are employed where necessary in accordance with generalprinciples of chemistry. Protecting groups are manipulated according tostandard methods of organic synthesis (T. W. Green and P. G. M. Wuts(1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). Thesegroups are removed at a convenient stage of the compound synthesis usingmethods that are readily apparent to those skilled in the art. Theselection of processes as well as the reaction conditions and order oftheir execution shall be consistent with the preparation of compounds ofFormula I, II or III. Those skilled in the art will recognize if astereocenter exists in compounds of Formula I, II or III. Accordingly,the present invention includes both possible stereoisomers and includesnot only racemic compounds but the individual enantiomers as well. Whena compound is desired as a single enantiomer, it may be obtained bystereospecific synthesis or by resolution of the final product or anyconvenient intermediate. Resolution of the final product, anintermediate, or a-starting material may be effected by any suitablemethod known in the art. See for example, Stereochemistry of OrganicCompounds by E. L. Eliel, S. H. Wilen, and L. N. Mander(Wiley-Interscience, 1994).

Compounds of Formula I, II or III can be prepared according to thesynthetic sequences illustrated in Schemes 1 and 2, which shows generalroutes for the synthesis of the targeted5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole derivatives.Specific details of synthetic routes according to Scheme 1 are shown inthe Examples, which include the preparation of5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid amide. All of the compounds specifically described herein may beprepared according to the procedures described in Examples 1-8hereinbelow.

A synthesis of 5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indolederivatives may be achieved by the route shown in Scheme 1. Thissynthesis uses an appropriately substituted pyridinyl chloride (ii),which is here exemplified with, but should not be seen as limited to, amethylcarbamoyl pyridyl chloride. Thus, a picolinic acid is treated withthionyl chloride in the presence of sodium bromide to give theintermediate 4-chloropyridine-2-carbonyl chloride, followed by treatmentwith the appropriate amine. The pyridinyl chloride (ii) is reacted with1-acetyl-2,3-dihydro-5-hydroxyindole in the presence of sodiumt-butoxide to generate the N-acetyl-diaryl ether, which upon treatmentwith acid provides the corresponding diaryl ether (iii). Treatment of(iii) with an appropriately substituted isocyanate gives thecorresponding urea (iv); treatment of (iii) with an appropriatelysubstituted acid in conjunction with standard peptide coupling reagentsor appropriately substituted acid chloride gives the amides (v and vi);treatment of (iii) with an appropriately substituted sulphonyl chlorideto give sulphonamide (vii).

An effective synthesis of5-(2-methylcarbamoyl-pyridin-4-ylamino)-2,3-dihydro-indole derivativesmay be achieved by the route shown in Scheme 2. This synthesis uses anappropriately substituted pyridinyl chloride (ii), which is hereexemplified with, but should not be seen as limited to, amethylcarbamoyl pyridyl chloride. The pyridinyl chloride (ii), describedin Scheme 1, is reacted with 1-acetyl-2,3-dihydro-5-aminoindole in thepresence of acid, such as ethereal hydrogen chloride, to generate theN-acetyl-diaryl amine salt which undergoes alkylation with standardconditions such as, but not limited, to methyl iodide in the presence ofa base such as potassium carbonate in a solvent like DMF to give, aftertreatment with aqueous acid, the corresponding diaryl amine (viii).Treatment of (viii) with an appropriately substituted isocyanate givesthe corresponding urea (ix); treatment of (viii) with an appropriatelysubstituted acid in conjunction with standard peptide coupling reagentsor appropriately substituted acid chloride gives the amides (x and xi);and treatment of (viii) with an appropriately substituted sulphonylchloride gives sulphonamide (xii).

EXAMPLES

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification: g (grams); mg(milligrams); L (liters); mL (milliliters); μL (microliters); psi(pounds per square inch); M (molar); mM (millimolar); i. v.(intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol(millimoles); rt (room temperature); min (minutes); h (hours); mp(melting point); TLC (thin layer chromatography); T_(r) (retentiontime); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA(triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroaceticanhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); AcOEt(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE(dichloroethane); DMF (N,N-dimethylformamide); DMPU(N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF(isobutyl chloroformate); HOAc (acetic acid); HOSu(N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); mCPBA(meta-chloroperbenzoic acid; EDC (ethylcarbodiimide hydrochloride); BOC(tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC(dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm(atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS(triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP(4-dimethylaminopyridine); BSA (bovine serum albumin) ATP (adenosinetriphosphate); HRP (horseradish peroxidase); DMEM (Dulbecco's modifiedEagle medium); HPLC (high pressure liquid chromatography); BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF(tetra-n-butylammonium fluoride); HBTU(O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate).HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid); DPPA(diphenylphosphoryl azide); fHNO₃ (fumed HNO₃); and EDTA(ethylenediaminetetraacetic acid).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at room temperature unlessotherwise noted.

¹H NMR (hereinafter also “NMR”) spectra were recorded on a VarianVXR-300, a Varian Unity-300, a Varian Unity-400 instrument, a BruckerAVANCE-400, a General Electric QE-300, or a Bruker AM 400 spectrometer.Chemical shifts are expressed in parts per million (ppm, δ units).Coupling constants are in units of hertz (Hz). Splitting patternsdescribe apparent multiplicities and are designated as s (singlet), d(doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br(broad).

Mass spectra were run on an open access LC/MS system using electrosprayionization. LC conditions: 4.5% to 90% CH₃CN (0.02% TFA) in 3.2 min witha 0.4 min hold and 1.4 min re-equilibration; detection by MS, UV at 214nm, and a light scattering detector (ELS). Column: 1×40 mm Aquasil (C₁₈).

For analytical hplc; ca 0.05 mg of the reaction mixtures were injectedin 5 uL of DMSO onto a 4.6×150 mm I. D. Zorbax Eclipse XDB-C₁I column at3 mL/min with a 10 min gradient from 5% CH₃CN (0.1% TFA) to 95% CH₃CN(0.1% TFA) in H₂O (0.1% TFA).

For preparative (prep) hplc; ca 50 mg of the final products wereinjected in 500 uL of DMSO onto a 50×20 mm I. D. YMC CombiPrep ODS-Acolumn at 20 mL/min with a 10 min gradient from 10% CH₃CN (0.1% TFA) to90% CH₃CN (0.1% TFA) in H₂O (0.1% TFA) and a 2 min hold. Flashchromatography was run over Merck Silica gel 60 (230-400 mesh).

Infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometerusing a 1-mm NaCl cell. Most of the reactions were monitored bythin-layer chromatography on 0.25 mm E. Merck silica gel plates(60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acidor p-anisaldehyde solution.

Example 15-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (2′-fluoro-5′-trifluoromethyl-phenyl)-amide

a) 4-Chloro-pyridine-2-carboxylic acid methylamide. Picolinic acid (6.6g, 50 mmol) was dissolved in thionyl chloride (30 mL) and potassiumbromide was added (595 mg, 5 mmol). The mixture was kept at refluxovernight then the resulting red solution was concentrated under reducedpressure. The resultant red oil was dissolved in toluene, filtered toremove KBr, and concentrated under reduced pressure (×3). The red oilwas then dissolved in THF (100 mL) and added dropwise to a stirredsolution of 2M methylamine in THF (100 mL, 200 mmol) at rt. The reactionwas stirred overnight at rt. The THF was removed under reduced pressure,and the residue was partitioned between ethyl acetate and 5% sodiumbicarbonate solution. The layers were separated and the organic layerwashed with water (×3) and brine. After drying (MgSO₄) concentrationgave a red oil (6.6 g) which was purified by chromatography on silicagel eluting with a gradient of Ethyl acetate/hexane to afford the titlecompound as an oil which crystallized on standing. (4.3 g, 50%) LC-MS(m/e)=171.0 [M+H]⁺. Retention time=1.29 min.

b) 4-(1-Acetyl-2,3-dihydro-1-H-indol-5-yloxy)-pyridine-2-carboxylic acidmethylamide. 1-Acetyl-2,3-dihydro-5-hydroxyindole (700 mg, 4 mmol) whichmay be prepared by the method as described by Rickard Hunt inJ.Chem.Soc.C, 344 (1966), was dissolved in DMF (4 ml) and treated at rtfor 5 min with potassium t-butoxide (500 mg, 1.1 eq) followed byaddition of 4-Chloro-pyridine-2-carboxylic acid methylamide (680 mg, 4mmol) and potassium carbonate (550 mg). This mixture was microwaved for10 min at 160° in a Personal Chemistry synthesizer. Hplc showedincomplete reaction, so the mixture was diluted to a volume a 10 mL(DMF), treated with additional of 4-Chloro-pyridine-2-carboxylic acidmethylamide (150 mg, 0.88 mmol) and potassium t-butoxide (100 mg), andmicrowaved for 20 min at 160°. The mixture was partitioned between ethylacetate and water and the aqueous extracted with EtOAc (×4). Thecombined extracts were washed with water (×3) and brine, then dried(MgSO₄) and evaporated under reduced pressure to afford the titlecompound as a off-white solid after trituration with Et₂O/hexane. (1.042g, 96.5%) LC-MS (m/e)=312.2 [M+H]⁺. Retention time=1.62 min. Hplc 93%.

c) 4-(2,3-Dihydro-1-H-indol-5-yloxy)-pyridine-2-carboxylic acidmethylamide.4-(1-Acetyl-2,3dihydro-1-H-indol-5-yloxy)-pyridine-2-carboxylic acidmethylamide (999 mg, 3.2 mmol) in 6N HCl (15 ml, 5 ml in each of 3vials) was placed in the microwave reactor and heated for 15 min at130°. The aqueous solution was made basic to pH 9 with 5% NaHCO₃ andextracted with EtOAc (×4). The combined extracts were washed with brine,dried (MgSO₄) and evaporated under reduced pressure to afford the titlecompound as a white foam (0.480 g, 56%) after flash chromatographyeluting with 30-70% EtOAc/Hexane. LC-MS (m/e)=270.4 [M+H]⁺. Retentiontime=1.15 min. Hplc 92%.

d) 5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (2′-fluoro-5′-trifluoromethyl-phenyl)-amide. To a solution of2-fluoro-5-trifluoromethyl-phenylisocyanate (24.6 mg, 0.12 mmol) indichloromethane (0.5 mL) was added4-(2,3-Dihydro-1-H-indol-5-yloxy)-pyridine-2-carboxylic acid methylamide(32 mg, 0.12 mmol) at 0°. The reaction was allowed to warm to rt after30 min at 0° and stirred overnight at rt. Hplc confirmed completereaction. A white precipitate, which had formed, was removed byfiltration after dilution with Et₂O to provide the title compound as awhite solid (34 mg, 60%). LC-MS (m/e)=475.2 [M+H]⁺. Retention time=2.22min. Hplc 100%. ¹H NMR(400 MHz, CDCl₃) 58.52-8.48 (m, 1H), 8.40 (d,J=7.6 Hz, 1H), 8.120 (br s, 1H) 8.018 (d, J=9.3 Hz, 1H), 7.71 (d, J=2.5Hz, 1H), 7.31-7.26 (m, 2H), 7.02-6.97 (m, 3 H), 6.83 (d, J=3.8 Hz, 1H),4.23 (t, 2H, J=8.5 Hz), 3.33 (t, 2H, J=8.5 Hz), 3.03 (d, J=5.1 Hz, 3H).

Example 25-(2-Methylcarbamoyl-pyridin-4yloxy)-2,3-dihydro-indole-1-carboxylicacid(2′-chloro-5′-trifluoromethyl-phenyl)-amide

Following the procedure of Example 1(d), except substituting(2-chloro-5-trifluoromethyl-phenylisocyanate for2-fluoro-5-trifluoromethyl-phenylisocyanate, the title compound wasprepared as a white solid (50 mg, 85%). LC-MS (m/e)=491.0 [M+H]⁺.Retention time=2.44 min. Hplc 100%. ¹H NMR(400 MHz, CDCl₃) δ8.75 (d,J=2.2 1H), 8.40 (d, J=5.6 Hz, 1H), 8.168 (br s, 1H, NH) 8.07 (d, J=8.4Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.26 (m,2H), 7.02-6.97 (m, 3H), 4.26 (t, 2H, J=8.5 Hz), 3.34 (t, 2H, J=8.5 Hz),3.03 (d, J=5.1 Hz, 3H).

Example 35-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid(3′-trifluoromethyl-phenyl)-amide

Following the procedure of Example 1(d), except substituting(3-trifluoromethyl-phenylisocyanate for2-fluoro-5-trifluoromethyl-phenylisocyanate, the title compound wasprepared as a white solid (45.6 mg, 83%). LC-MS (nm/e)=457.20 [M+H]⁺.Retention time=2.29 min. Hplc 98.5%. ¹H NMR(400 MHz, CDCl₃) δ8.40 (d,J=5.6 Hz, 1H), 8.18 (br s, 1H, NH), 8.00 (d, J=9.4 Hz, 1H), 7.76-7.68(m, 3H), 7.46 (t, J=7.8 Hz, 1H), 7.35(d, J=7.8 Hz, 1H), 7.03-6.88 (m,4H), 4.17 (t, 2H, J=8.5 Hz), 3.28 (t, 2H, J=8.5 Hz), 3.03 (d, J=5.1 Hz,3H).

Example 45-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid(4′-fluoro-3′-trifluoromethyl-phenyl)-amide

Following the procedure of Example 1(d), except substituting(4-fluoro-3-trifluoromethyl-phenylisocyanate for2-fluoro-5-trifluoromethyl-phenylisocyanate, the title compound wasprepared as a white solid (41.1 mg, 72%). LC-MS (m/e)=475.2 [M+H]⁺.Retention time=2.27 min. Hplc 100%. ¹H NMR(400 MHz, CDCl₃) δ8.40 (d,J=5.6 Hz, 1H), 8.20 (br s, 1H, NM) 8.00 (d, J=9.1 Hz, 1H), 7.17 (t,J=9.1 Hz, 1H), 7.03 (dd, J=5.6 Hz and J=2.6 Hz, 1H), 6.95-6.89 (m, 3H),4.15 (t, J=8.5 Hz, 2H), 3.28 (t, J=8.5 Hz, 2H), 3.03 (d, J=5.1 Hz, 3H).

Example 5

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid(3′-chlorophenyl)-amide

Following the procedure of Example l(d), except substituting(3-chloro-phenylisocyanate for2-fluoro-5-trifluoromethyl-phenylisocyanate, the title compound wasprepared as a white solid (39.7 mg, 78%). LC-MS (m/e)=423.0 [M+H]⁺.Retention time=2.17 min. Hplc 97%. ¹H NMR(400 MHz, CDCl₃) δ8.40 (d,J=5.6 Hz, 1H), 8.25 (br s, 1H, NH), 8.00 (d, J=9.4 Hz, 1H), 7.71 (d,J=2.4 Hz, 1H), 7.60 (t, J=2.1 Hz, 1H), 7.355-7.241(m, 3H), 7.09 (d,J=0.9 Hz, 1H), 4.17 (t, 2H, J=8.5 Hz), 3.28 (t, 2H, J=8.5 Hz), 3.03 (d,J=5.1 Hz, 3H).

Example 65-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid(bis-3′,5′-trifluoromethylphenyl)-amide

Following the procedure of Example 1(d), except substituting(bis-3,5-trifluoromethylphenyl-isocyanate for2-fluoro-5-trifluoromethyl-phenylisocyanate, the title compound wasprepared as a white solid (45.6 mg, 72%). LC-MS (m/e)=525.2 [M+H]⁺.Retention time=2.54 min. Hplc 100%. ¹H NMR(400 MHz, CDCl₃) δ8.40 (d,J=5.6 Hz, 1H), 8.26 (br s, 1H, NH), 8.010 (m, 3H), 7.66 (d, J=2.5 Hz,1H), 7.57 (s, 1H), 7.188 (s, 1H), 7.05 (dd, J=5.6 Hz, J=2.6 Hz 1H), 4.17(t, 2H, J=8.5 Hz), 3.29 (t, 2H, J=8.5 Hz), 3.03 (d, J=5.1 Hz, 3H).

Example 75-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid(5-tert-butyl-isoxazol-3-yl)-amide trifluoroacetate

The compound of 1-Acetyl-2,3-dihydro-5-hydroxyindole (54 mg g, 2 mmol)was dissolved in DMF (4 mL) and treated with Hunig's base (72 uL, 4mmol) and (5-t-butyl-isoxazol-3-yl)-carbamic acid phenyl ester (78 mg, 3mmol), then microwaved at 190° for 800 sec. The crude reaction mixturewas chromatographed on reverse phase column eluting 5%-95%acetonitrile/0.1% TFA water. The material isolated from thischromatography was then chromatographed using a different C₁₈ reversephase column (45 mg) and finally recrystallized from acetonitrile/waterto give white crystals. (20 mg, 23 %) LC-MS (m/e)=436.4 [M+H]⁺.Retention time=2.11 min. Hplc 93%. ¹H NMR(400 MHz, CD₃OD) δ8.50 (d,J=5.86 Hz, 1H), 8.04 (d, J=8.7 Hz 1H), 7.65 (d, J=2.4 Hz, 1H), 7.2-6.9(m, 3H), 7.188 (s, 1H), 6.554 (s, 1H), 4.17 (t, J=8.5 Hz, 2H), 3.3 (t,2H), 2.96 (s, 3H) 1.3 (s, 9H).

Example 85-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid(4′-chloro-3′-trifluoromethyl-phenyl)-amide

Following the procedure of Example 1(d), except substituting(4-chloro-3-trifluoromethyl-phenylisocyanate for2-fluoro-5-trifluoromethyl-phenylisocyanate, the title compound wasprepared as a white solid (850 mg, 86%). LC-MS (m/e)=491.04 [M+H]⁺.Retention time=2.44 min. Hplc 94%. ¹H NMR(400 MHz, CDCl₃) δ88.37 (d,J=5.6 Hz, 1H) 8.015 (br s, 1H, NH), 7.97 (m, 1H) 7.71 (d, J=2.5 Hz, 1H),7.70 (dd, J=2.5 Hz, J=8.8 Hz, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.452 (d,J=8.8 Hz, 1H), 6.37-6.922 (m, 3H), 6.71 (s, 1H), 4.14 (t, 2H, J=8.4 Hz),3.26 (t, 2H, J=8.4 Hz), 3.01 (d, J=5.2 Hz, 3H).

Examples 9-31

Following the procedure of Example 1(d), except substituting theappropriate isocyanate for 2-fluoro-5-trifluoromethyl-phenylisocyanate,the following title compounds were prepared:

LC Mass Spectra Example [M + H] @ # R Compound Name ret time 9

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (4'-fluorophenyl)-amide 407.2 @2.00 min 10

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (2-methoxy-5-methyl-phenyl)-amide 433.4 @2.24 min 11

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (2,5-dimethoxy-phenyl)-amide 448.8 @2.15 min 12

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid 3-chloro-2-methyl-phenyl)-amide 436.6 @2.10 min 13

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid cyclohexylamide 395.2 @2.02 min 14

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (2-phenoxy-pbenyl)-amide 481.0 @2.42 min 15

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid tert-butylamide 369.2 @1.87 min 16

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid- indan-5-ylamide 429.0 @2.22 min 17

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3-acetyl-phenyl)-lamide 431.2 @1.85 min 18

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (2-methyl-5-nitro-phenyl)-lamide 448.0 @2.07 min 19

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3-methoxy-phenyl)-lamide 419.2@ 1.97 min 20

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3-chloro-4-fluoror-phenyl)-lamide 441.0 @2.22 min 21

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3-,5-dimethyl-phenyl)-amide 417.2 @2.12 min 22

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid naphthalen-2-yl-amide 439.2 @2.25 min 23

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid benzo[1,3]dioxol-5-ylamide 433.0 @1.90 min 24

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3,5-dimethoxy-phenyl)-amide 449.0 @2.02 min 25

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (4-phenoxy-phenyl)-amide 481.0 @2.35 min 26

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3,5-dichloro-phenyl)-amide 457.0 @2.47 min 27

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3-acetyl-phenyl)-lamide 505.2@ 2.17 min 28

({1-[5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indol-1-yl]-methanoyl}- amino)-acetic acid ethyl ester 399.2@1.55 min 29

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (2-fluoro-3- tirfluoromethyl-phenyl)-amide 475.0 @2.25 min 30

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3-fluoro- phenyl)-amide 464.2 @2.29 min 31

5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3-methyl- phenyl)-amide 403.2 @2.15 min

Examples 32-48

Following the procedures described above in Example 1(a) exceptsubstituting the appropriate amine for N-methyl amine the followingtitle compounds were prepared. Thus, the following4-Chloro-pyridine-2-carboxylic acid amides were prepared as describedabove in Example 1(a) starting from picolinic acid and correspondingamine:

Intermediate # R Compound Name ¹H—NMR (CDCl₃) 32a CH₃CH₂—4-Chloro-pyridine-2- carboxylic acid ethylamide 1.29 (t, 3H, J=7.6 Hz),3.53 (q, 2H, J=7.6 Hz), 7.48 (q, 1H, J=2 Hz), 8.02 (br s, 1H) 8.23 (d,1H, J=2 Hz) 8.45 (d, 1H, J=4.8 Hz) 33a CH₃CH₂CH₂— 4-Chloro-pyridine-2-carboxylic acid propylamide 1.00 (t, 3H, J=7.6 Hz), 1.66 (m, 2H), 3.44(q, 2H, J=7.6 Hz), 7.43 (q, 1H, J=2 Hz), 8.02 (br s, 1H) 8.21 (d, 1H,J=2 Hz) 8.46 (d, 1H, J=4.8 Hz) 34a

4-Chloro-pyridine-2- carboxylic acid phenylamide 7.18-7.50 (m, 6H) 8.33(m, 1H) 8.45 (s, 1H) 9.93 (br s, 1H) 35a

4-Chloro-pyridine-2- carboxylic acid benzylamide 4.69 (d, 2H, J=6 Hz),7.20-7.48 (m, 6H) 8.31 (m, 2H) 8.45 (s, 1H) 36a

4-Chloro-pyridine-2- carboxylic acid phenethyl- amide 2.87 (m, 2H), 3.05(m, 2H), 7.18-7.44 (m, 6H) 8.06 (br s, 1H) 8.26 (s, 1H) 8.43 (s, 1H) 37a

4-Chloro-pyridine-2- carboxylic acid (1-methyl- piperidin-4-yl)-amide1.64 (m, 2H), 2.02 (m, 2H), 2.18 (m, 2H), 2.32 (s, 3H) 2.85 (m, 2H) 3.95(m, 1H) 7.44 (q, 1H, J=2 Hz), 7.95 (br s, 1H) 8.25 (d, 1H, J=2 Hz) 8.41(d, 1H, J=4.8 Hz) 38a

4-Chloro-pyridine-2- carboxylic acid (2- diethylamino-ethyl)-amide 1.06(m, 6H), 1.80 (m, 2H), 1.93 (m, 2H), 2.59 (m, 6H) 3.88 (m, 2H) 7.41 (q,1H, J=2 Hz), 8.21 (d, 1H, J=2 Hz) 8.45 (d, 1H, J=4.8 Hz) 8.97 (br s, 1H)39a

4-Chloro-pyridine-2- carboxylic acid (2-morpholin- 4-yl-ethyl)-amide2.56 (m, 4H), 2.64 (m, 2H), 3.62 (m, 2H), 3.77 (m, 4H) 7.44 (q, 1H, J=2Hz), 8.21 (d, 1H, J=2 Hz) 8.32 (br s, 1H) 8.49 (d, 1H, J=4.8 Hz) 40a

4-Chloro-pyridine-2- carboxylic acid (3-morpholin- 4-yl-propyl)-amide1.45 (m, 4H), 1.88 (m, 2H), 2.60 (m, 4H), 3.63 (m, 2H) 3.86 (m, 4H) 7.45(q, 1H, J=2 Hz), 8.22 (d, 1H, J=2 Hz) 8.58 (d, 1H, J=4.8 Hz) 8.98 (br s,1H) 41a

4-Chloro-pyridine-2- carboxylic acid (2-piperidin-1- yl-ethyl)-amide1.44 (m, 2H), 1.64 (m, 2H), 2.46-2.68 (m, 6H), 3.82 (m, 2H) 3.86 (m, 4H)7.43 (q, 1H, J=2 Hz), 8.33 (d, 1H, J=2 Hz) 8.41 (br s, 1H) 8.47 (d, 1H,J=4.8 Hz) 42a

4-Chloro-pyridine-2- carboxylic acid (4-pyrrolidin- 1-yl-butyl)-amide1.65 (m, 4H), 1.83 (m, 4H), 2.03 (m, 2H), 2.54 (m, 2H) 3.76 (m, 4H) 7.43(q, 1H, J=2 Hz), 8.21 (m, 2H) 8.45 (d, 1H, J=4.8 Hz) 43a

4-Chloro-pyridine-2- carboxylic acid isopropylamide 1.31 (d, 6H, J=6Hz), 4.29 (m, 1H), 7.43 (q, 1H, J=2 Hz) 7.69 (br s, 1H) 8.22 (d, 1H, J=2Hz) 8.46 (d, 1H, J=4.8 Hz) 44a

4-Chloro-pyridine-2- carboxylic acid (2-methoxy- ethyl)-amide 3.42 (s,3H), 3.66 (m, 2H), 3.70 (m, 2H) 7.44 (q, 1H, J=2 Hz) 8.22 (br s, 2H)8.48 (d, 1H, J=4.8 Hz) 45a

4-Chloro-pyridine-2- carboxylic acid (2-phenoxy- ethyl)-amide 4.00 (m,2H), 4.19 (m, 2H) 6.98 (m, 4H) 7.31 (m 2H) 8.23 (d, 1H, J=2 Hz) 8.41 (brs, 1H) 8.48 (d, 1H, J=4.8 Hz) 46a

4-Chloro-pyridine-2- carboxylic acid (3-ethoxy- propyl)-amide 1.26 (t,3H, J=7.2 Hz) 1.92 (m, 3H), 3.56 (m, 6H), 7.44 (q, 1H, J=2 Hz) 8.21 (d,1H, J=2 Hz) 8.46 (m, 2H) 47a

4-Chloro-pyridine-2- carboxylic acid (3-isopropoxy- propyl)-amide 1.22(m, 8H) 1.92 (m, 2H), 3.62 (m, 5H), 7.43 (q, 1H, J=2 Hz) 8.21 (d, 1H,J=2 Hz) 8.46 (d, 1H, J=4.8 Hz) 8.84 (m, 2H) 48a

4-Chloro-pyridine-2- carboxylic acid hexylamide 0.93 (m, 3H) 1.45 (m,6H), 1.66 (m, 2H), 3.50 (m, 2H), 7.44 (q, 1H, J=2 Hz) 7.99 (m, 2H) 8.23(d, 1H, J=2 Hz) 8.46 (m, 2H)

Then, the following4-(1-Acetyl-2,3-dihydro-1H-indol-5-yloxy)-pyridine-2-carboxylic acidamides were prepared as described above in Example 1(b) starting from1-acetyl-2,3-dihydro-5-hydroxyindole and corresponding4-Chloro-pyridine-2-carboxylic acid amide:

LC Mass Spectra Example # R Compound Name [M + H] @ ret time 32 CH₃CH₂—4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acidethylamide 326.4 @ 1.66 min 33 CH₃CH₂CH₂—4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acidpropylamide 340.2 @ 1.77 min 34

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acidphenylamide 352.2 @ 1.83 min 35

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acidbenzylamide 374.2 @ 2.17 min 36

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acidphenethyl-amide 388.2 @ 1.97 min 37

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(1-methyl-piperidin-4-yl)-amide 402.2 @ 2.05 min 38

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(2-diethylamino-ethyl)-amide 395.2 @ 1.28 min 39

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(2-morpholin-4-yl-ethyl)-amide 411.4 @ 1.30 min 40

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(3-morpholin-4-yl-propyl)-amide 425.0 @ 1.37 min 41

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(2-piperidin-1-yl-ethyl)-amide 409.2 @ 1.30 min 42

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(2-pyrrolidin-1-yl-butyl)-amide 423.0 @ 1.35 min 43

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acidisopropylamide 340.0 @ 2.90 min 44

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(2-methoxy-ethyl)-amide 356.0 @ 2.82 min 45

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(2-phenoxy-ethyl)-amide 418.4 @ 3.05 min 46

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(3-ethoxy-propyl)-amide 384.2 @ 1.89 min 47

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acid(3-isopropoxy-propyl)-amide 398.2 @ 2.05 min 48

4-(1-Acetyl-2,3-dihydro-1H-indol- 5-yloxy)-pyridine-2-carboxylic acidhexylamide 382.4 @ 2.42 min

Examples 49-65

Following the procedures described above in Example 1(a), 1(b), and1(c), except substituting the appropriate amine for N-methyl amine andusing the procedure below for the coupling using3-trifluoromethylphenylisocyanate, the following title compounds5-(2-substitutedcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (3-trifluoromethyl-phenyl)-amides were prepared.

Hydrolysis of the N-acetyl compounds was executed as described above inExample 1(c) starting from corresponding4-(1-Acetyl-2,3-dihydro-1H-indol-5-yloxy)-pyridine-2-carboxylic acidamides to give the title compounds, which were used in the next stepwithout further purification. The coupling was performed as follows: Toa solution of 4-(2,3-dihydro-1H-indol-5-yloxy)-pyridine-2-carboxylicacid amide (0.2 mmol) in NMP (0.5 mL) was added3-trifiuoromethyl-phenylisocyanate (0.3 mmol). The reaction was stirredat rt for for 30 min and then purified by preparative HPLC. Pure desiredproduct was then isolated as its trifluoroacetic salt.

LC Mass Spectra [M + H] Example # R Compound Name @ ret time 49 CH₃CH₂—5-(2-Ethylcarbamoyl-pyridin-4-yloxy)-2,3- dihydro-indole-1-carboxylicacid (3- trifluoromethyl-phenyl)-amide 471.2 @2.25 min 50 CH₃CH₂CH₂—5-(2-Propylcarbamoyl-pyridin-4-yloxy)- 2,3-dihydro-indole-1-carboxylicacid (3- trifluoromethyl-phenyl)-amide 485.2 @2.25 min 51

5-(2-Phenylcarbamoyl-pyridin-4-yloxy)- 2,3-dihydro-indole-1-carboxylicacid (3- trifluoromethyl-phenyl)-amide 519.2 @2.62 min 52

5-(2-Benzylcarbamoyl-pyridin-4-yloxy- 2,3-dihydro-indole-1-carboxylicacid (3- trifluoromethyl-phenyl)-amide 533.2 @2.49 min 53

5-(2-Phenethylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide 547.2 @2.54 min 54

5-[2-(1-Methyl-piperidin-4-ylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1- carboxylic acid (3-trifluoromethyl-phenyl)-amide 540.2 @1.95 min 55

5-[2-(3-Diethylamino-propylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1- carboxylic acid(3-trifluoromethyl-phenyl)- amide 556.2 @2.04 min 56

5-[2-(2-Morpholin-4-yl-ethylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1- carboxylic acid(3-trifluoromethyl-phenyl)- amide 556.0 @1.94 min 57

5-[2-(3-Morpholin-4-yl-propylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1- carboxylic acid(3-trifluoromethyl-phenyl)- amide 570.0 @1.94 min 58

5-[2-(2-Piperidin-1-yl-ethylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1- carboxylic acid(3-trifluoromethyl-phenyl)- amide 554.4 @2.09 min 59

5-[2-(4-Pyrrolidin-1-yl-butylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1- carboxylic acid(3-trifluoromethyl-phenyl)- amide 568.2 @2.22 min 60

5-(2-Isopropylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide484.6 @2.50 min 61

5-[2-(2-Methoxy-ethylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide 501.2 @2.35 min 62

5-[2-(2-Phenoxy-ethylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide 563.0 @2.71 min 63

5-[2-(3-Ethoxy-propylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1-carboxylic acid(3-trifluoromethyl-phenyl)-amide 529.2 @2.55 min 64

5-[2-(3-Isopropoxy-propylcarbamoyl)-pyridin-4-yloxy]-2,3-dihydro-indole-1- carboxylic acid(3-trifluoromethyl-phenyl)- amide 543.4 @2.62 min 65

5-(2-Hexylcarbamoyl-pyridin-4-yloxy)- 2,3-dihydro-indole-1-carboxylicacid (3- trifluoromethyl-phenyl)-amide 527.2 @2.87 min

Example 665-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amide

a) 1-Methyl-4-(4-nitro-benzyl)-piperazine. 4-Nitrobenzyl chloride (0.5g, 2.91 mmol) was dissolved in acetone (10 mL), and to this solution wasadded K₂CO₃ (0.8 g, 5.8 mmol) and 1-methylpiperazine (0.39 mL, 3.5mmol). After heating at reflux for one hour, the mixture was cooled, theexcess K₂CO₃ removed by filtration, and the acetone evaporated in vacuo.Column chromatography afforded 1-methyl-4-(4-nitro-benzyl)-piperazine asan off-white solid (0.59 g, 86% yield): MS (M+1) 236; ¹H NMR (400 MHz,CDCl₃) δ8.17 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 3.66 (s, 2H),2.75 (bs, 4H), 2.55 (bs, 4H), 2.42 (s, 3H).

b) 4-(4-Methyl-piperazin-1-ylmethyl)-phenylamine.1-Methyl-4-(4-nitro-benzyl)-piperazine (100 mg, 0.43 mmol) was added toa flask containing 5 mg Pt/C (5% w/w, 62% H₂O content) in EtOH (2.1 mL).The reaction mixture was stirred under an atmosphere of H₂ until thereaction was complete by LCMS analysis (4h). The mixture was filtered,rinsed with EtOH, and concentrated to afford4-(4-methyl-piperazin-1-ylmethyl)-phenylarnine as a yellow oil, whichwas sufficiently pure for the next step (97 mg, 100%): MS (M+1) 206; ¹HNMR (400 MHz, CDCl₃) δ7.10 (d, J=8.4 Hz, 2H), 6.63 (d, J=8.4 Hz, 2H),3.67 (bs, 2H), 3.49 (s, 2H), 2.66 (bs, 8H), 2.42 (s, 3).

c) 5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amide. To a 25 mL flaskwas added under a nitrogen atmosphere phenyl chloroformate (0.0245 mL,0.195 mmol) and THF (0.65 mL). The mixture was cooled to 0° C. and4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (0.04 g, 0.195 mmol) inTHF (0.6 mL) was added dropwise via syringe over 30 min. Et₃N (0.028 mL,0.197 mmol) was added, and the heterogeneous mixture is allowed to warmslowly to room temperature over two hours. At this time, the mixture ofthe crude carbamate was transferred via cannula to a flask containingthe pyridyl indoline (0.052 g, 0.195 mmol) and THF (0.4 mL). AdditionalEt₃N (0.085 mL, 0.605 mmol) was added, the septum replaced with acondenser, and the whole mixture was refluxed under nitrogen overnight.Upon cooling, the mixture was treated with H₂O, CH₂Cl₂, and sat. aq.NaHCO₃. The layers were separated, and the aqueous portion extractedfurther with CH₂Cl₂ (2×). Purification on reverse-phase HPLC, followedby treatment with aq. NaHCO₃ and extraction with CH₂Cl₂ provided5-(2-methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amide as the free-base(8.8 mg, 10% yield): MS (M+1) 501; ¹H NMR (400 MHz, CDCl₃) δ8.36 (d,J=5.6 Hz, 1H), 7.98 (m, 2H), 7.67 (d, J=2.4 Hz, 1H), 7.40 (d, J=8.0 Hz,2), 7.29 (d, J=7.6 Hz, 2H), 6.95 (m, 3H), 6.44 (s, 1H), 4.16 (t, J=8.0Hz, 2H), 3.48 (s, 2H), 3.26 (t, J=7.6 Hz, 2H), 3.01 (d, J=5.2 Hz, 3H),2.49 (m, 8H), 2.29 (s, 3H).

Example 675-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid [3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amide:

Following the procedure of Example 66(a)-66(c), except substituting3-nitrobenzyl bromide for 4-nitrobenzyl chloride in Example 66(a), thefollowing compounds were prepared:

a) 1-Methyl-4-(3-nitro-benzyl)-piperazine: 67% yield; MS (M+1) 236; ¹HNMR (400 MHz, CDCl₃) 38.21 (s, 1H), 8.11 (ddd, J=0.8, 1.2, 8.4 Hz, 1H),7.64 (d, J=7.2 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 3.61 (s, 2H), 2.59 (bs,8H), 2.39 (s, 3H).

b) 3-(4-Methyl-piperazin-1-ylmethyl)-phenyl-amine: 83% yield; MS (M+1)206; ¹H NMR (400 MHz, CDCl₃) δ7.06 (t, J=8.0 Hz, 1H), 6.5-6.7 (m, 3H),3.63 (bs, 2H), (s, 2H), 2.47 (bs, 8H), 2.29 (s, 3H).

c) 5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid [3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amide: 35% yield; ¹H NMR(400 MHz, CDCl₃) δ8.36 (d, J=5.6 Hz, 1H), 7.98 (m, 2H), 7.67 (d, J=2.8Hz, 1H), 7.45 (dd, J=2.1, 8.0 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J=7.6 Hz,1H), 7.05 (d, J=7.6 Hz, 1H), 6.95 (m, 3H), 6.48 (s, 1H), 4.14 (t, J=8.8Hz, 2H), 3.50 (s, 2H), 3.26 (t, J=8.4 Hz, 2H), 3.01 (d, J=5.2 Hz, 3H),2.50 (bs, 8H), 2.30 (s, 3H).

Example 685-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide

a) 1-Methyl-4-(nitro-trifluoromethyl-benzyl)-piperazine: To a suspensionof 4-nitro-2-(trifluoromethyl)toluene (0.5 g, 2.44 mmol) in AcOH (1.9mL) was added NBS (0.651 g, 3.66 mmol) and benzoyl peroxide (6 mg, 0.024mmol), and mixture was heated at reflux overnight. Upon cooling, thesolvent was removed in vacuo, EtOAc and aq. NaHCO₃ were added, and thelayers were separated. The organic layer was dried (Na₂SO₄), filtered,and concentrated to afford crude benzyl bromide (700 mg), which was usedin the next reaction without further purification.

To a solution of crude 1-bromomethyl-4-nitro-2-trifluoromethyl-benzene(400 mg, 1.41 mmol) in CH₂Cl₂ (2.8 mL) was added Et₃N (0.197 mL, 1.41mmol) and 1-methylpiperazine (0.157 mL, 1.41 mmol). After stirring fortwo hours, aq. NaHCO₃ was added, and the mixture was extracted withCH₂Cl₂ (2×). The combined organic layers were dried over Na₂SO₄,filtered, concentrated and the resulting residue purified by silica gelchromatography to afford1-methyl-4-(nitro-trifluoromethyl-benzyl)-piperazine (249 mg, 58%yield): MS (M+1) 304; ¹H NMR (400 MHz, CDCl₃) δ8.51 (d, J=2.0 Hz, 1H),8.37 (dd, J=2.0, 8.4 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 3.75 (s, 2H), 2.49(m, 8H), 2.32 (s, 3H).

Following the procedure of Example 66(b) and 66(c), except substituting1-methyl-4-(nitro-triluoromethyl-benzyl)-piperazine for1-methyl-4-(4-nitro-benzyl)-piperazine in Example 66(a), the followingcompounds were prepared:

b) 4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl-amine: 70%yield; MS (M+1) 274; ¹H NMR (400 MHz, CDCl₃) δ7.47 (d, J=8.4 Hz, 1H),6.91 (d, J=2.4 Hz, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H), 3.75 (bs, 2H),3.53 (s, 2H), 2.48 (bs, 8H), 2.29 (s, 3H).

c) 5-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide:16% yield; MS (M+1) 569; ¹H NMR (400 MHz, CDCl₃) δ8.36 (d, J=5.2 Hz,1H), 8.00 (m, 2H), 7.69 (m, 4H), 6.95 (m, 3H), 6.56 (s, 1H), 4.16 (t,J=8.4 Hz, 2H), 3.62 (s, 2H), 3.28 (t, J=8.4 Hz, 2H), 3.01 (d, J=5.2 Hz,3H), 2.50 (m, 8H), 2.31 (s, 3H).

Example 69

Following the procedure of Example 68(a)-68(c), except substitutingmorpholine for 1-methylpiperazine in Example 66(a), the followingcompound was prepared:

a) 4-(Nitro-trifluoromethyl-benzyl)-morpholine. 59% yield; MS (M+1) 291;¹H NMR (400 MHz, CDCl₃) δ8.51 (d, J=2.4 Hz, 1H), 8.38 (dd, J=2.4, 8.4Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 3.75 (dd, J=4.4, 4.8 Hz, 6H), 2.51 (dd,J=4.4, 4.8 Hz, 4H).

b) 4-Morpholin-4-ylmethyl-3-trifluoromethyl-phenyl-amine: 84% yield; MS(M+1) 261; ¹H NMR (400 MHz, CDCl₃) δ7.51 (d, J=7.2 Hz, 1H), 6.92 (d,J=2.4 Hz, 1H), 6.80 (dd, J=2.0, 8.4 Hz, 1H), 3.78 (bs, 2H), 3.71 (dd,J=4.4, 4.8 Hz, 4H), 2.44 (dd, J=4.4, 4.8 Hz, 4H).

c) 5-2-Methylcarbamoyl-pyridin-4-yloxy)-2,3-dihydro-indole-1-carboxylicacid (4-morpholin-4-ylmethyl-3-tritluoromethyl-phenyl)-amide: 28% yield;MS (M+1) 556; ¹H NMR (400 MHz, CDCl₃) δ8.37 (d, J=5.6 Hz, 1H), 8.01 (m,2H), 7.69 (m, 4H), 6.96 (m, 3H), 6.58 (s, 1H), 4.16 (t, J=8.4 Hz, 2H),3.72 (dd, J=4.4, 4.8 Hz, 4H), 3.62 (s, 2H), 3.28 (d, J=8.4 Hz, 2H), 3.01(d, 5.2 Hz, 3H), 2.47 (dd, J=4.4, 4.8 Hz, 4H).

Examples 70-82

4-(2,3-Dihydro-1-H-indol-6-yloxy)-pyridine-2-carboxylic acid methylamide(Example 1(c), 27 mg, 0.1 mmol) and 1,1′carbonyl-diimidazole (32 mg, 0.2mmol) were dissolved in DMF 1.0 ml) and stirred at rt for 5 min followedby addition of the corresponding substituted acetic acid (0.2 mmol) andtriethylamine (19 ul, 0.1 mmol). This mixture was stirred at rtovernight. The crude reaction mixture was chromatographed on reversephase column eluting 10%-90% acetonitrile/0.1% TFA water to afford thefollowing title compounds after removal:

LC Mass Spectra [M + H] @ Example # R Compound Name ret time 70

4-{1-[2-(Bis-trifluoromethyl-phenyl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy}-pyridine-2- carboxylicacid methylamide 542@2.88 min 71

4-{1-[2-(Fluoro-trifluoromethyl-phenyl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy}- pyridine-2-carboxylic acidmethylamide 474 @2.34 min 72

4-{1-[2-(3-Methyl-isoxazol-4-yl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy}-pyridine-2- carboxylic acid methylamide 393@1.95 min 73

4-{1-[2-(Chloro-trifluoromethyl-phenyl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy}- pyridine-2-carboxylic acidmethylamide 490 @2.32 min 74

4-{1-[2-(3,5-Dichloro-phenyl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy}-pyridine-2- carboxylic acid methylamide 456@2.21 min 75

4-{1-[2-(Fluoro-trifluoromethyl-phenyl)-ethanoyl]-2,3-dihydro-1Hindol-5-yloxy}- pyridine-2-carboxylic acidmethylamide 422 @1.98 min 76

4-[1-(2-Naphthalen-2-yl-ethanoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyridine-2-carboxylic acid methylamide 438 @2.67 min77

4-{1-[2-(Fluoro-trifluoromethyl-phenyl)-ethanoyl]-2,3-dihydro-1Hindol-5-yloxy}- pyridine-2-carboxylic acidmethylamide 474 @2.40 min 78

4-(1-{1-[1-(Bis-trifluoromethyl-phenyl)-cyclopropyl]-methanoyl}-2,3-dihydro-1H-indol-5-yloxy)-pyridine-2-carboxylic acid methylamide 540 @1.85 min 79

4-(1-{1-[1-(3,4-Dichloro-phenyl)-cyclopropyl]-methanoyl}-2,3-dihydro-1H-indol-5-yloxy)- pyridine-2-carboxylic acidmethylamide 482 @2.55 min 80

4-(1-{1-[1-(2,4-Difluoro-phenyl)-cyclopropyl]-methanoyl}-2,3-dihydro-1H-indol-5-yloxy)- pyridine-2-carboxylic acidmethylamide 450 @1.65 min 81

4-{1-[2-(3-Hydroxy-phenyl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy}-pyridine-2- carboxylic acid methylamide 404@1.89 min 82

4-{1-[2-(4-Chloro-3-hydroxy-phenyl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy}- pyridine-2-carboxylic acidmethylamide 438 @1.95 min

Examples 83-86

4-{1-[2-3-Hydroxy-phenyl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy)-pyridine-2-carboxylicacid methylamide (20 mg, 0.05 mmol) and the corresponding alkyl chlorideHCl salt (0.075 mmol) were dissolved in 1.0 ml DMF and treated withpotassium t-butoxide (12 mg, 0.1 mmol and potassium carbonate (14 mg,0.1 mmol). The reaction mixture was stirred at rt overnight. The crudereaction mixture was chromatographed on reverse phase column eluting10%-70% acetonitrile/0.1 % TFA water resulting in the following titlecompounds:

LC Mass Spectra [M + H] @ Example # R Compound Name ret time 83

4-(1-{2-[3-(3-Piperazin-1-yl-propoxy)-phenyl]-ethanoyl}-2,3-dihydro-1H-indol-5- yloxy)-pyridine-2-carboxylicacid methylamide 530 @2.25 min 84

4-(1-{2-[3-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-ethanoyl}-2,3-dihydro-1H-indol-5- yloxy)-pyridine-2-carboxylicacid methylamide 501 @1.83 min 85

4-(1-{2-[3-(2-Dimethylamino-ethoxy)-phenyl]-ethanoyl}-2,3-dihydro-1H-indol-5- yloxy)-pyridine-2-carboxylicacid methylamide 475 @2.12 min 86

4-(1-{2-[3-(2-Morpholin-4-yl-ethoxy)-phenyl]-ethanoyl}-2,3-dihydro-1H-indol-5- yloxy)-pyridine-2-carboxylicacid methylamide 518 @2.08 min

Examples 87-89

A mixture of4-{1-[2-(4-Chloro-3-hydroxy-phenyl)-ethanoyl]-2,3-dihydro-1H-indol-5-yloxy}-pyridine-2-carboxylicacid methylamide (21 mg, 0.043 mmol), the corresponding alkyl chlorideHCl salt (1.5 eq.), Et₃N (10 uL) and 18-crown-6 (1 mg) in acetonitrile(1 mL) with saturated K₂CO₃ solution (0.25 mL) were heated in amicrowave at 180° or 15 min. The crude reaction mixture waschromatographed on reverse phase column eluting 10%-70%acetonitrile/0.1% TFA water resulting in the following title compounds:

LC Mass Spectra [M + H] @ Example # R Compound Name ret time 87

4-(1-{2-[3-Chloro-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-ethanoyl}-2,3-dihydro-1H-indol-5-yloxy)-pyridine-2-carboxylic acid methylamide 535 @1.75 min88

4-(1-{2-[3 Chloro-(2-dimethylamino-ethoxy)-phenyl]-ethanoyl}-2,3-dihydro-1H-indol-5-yloxy)-pyridine-2-carboxylic acid methylamide 509 @1.65 min89

4-(1-{2-[3-Chloro-(2-morpholin-4-yl-ethoxy)-phenyl]-ethanoyl}-2,3-dihydro-1H-indol-5-yloxy)-pyridine-2-carboxylic acid methylamide 551 @1.66 min

Examples 90-99

4-(2,3-Dihydro-1-H-indol-6-yloxy)-pyridine-2-carboxylic acid methylamide(27 mg; 0.1 mmol) and Aryl-2-sulfonyl chloride (0.12 mmol) weredissolved in CH₂Cl₂ (1.0 ml). To this mixture, triethylamine (50 uL) wasadded at 0° C. and warmed up to rt. This mixture was stirred at rtovernight. The crude reaction mixture was chromatograph on reverse phasecolumn by eluting with 10%-90% acetonitrile/0.1% TFA water resulting inthe following title compounds:

LC Mass Spectra [M + H] @ Example # R Compound Name ret time 90

4-[1-(Methyl-trifluoromethyl- benzenesulfonyl)-2,3-dihydro-1H-indol-5-yloxy]-pyridine-2-carboxylic acid methylamide 492 @2.34 min 91

4-{1-[5-(5-Trifluoromethyl-isoxazol- 3-yl)-thiophene-2-sulfonyl]-2,3-dihydro-1H-indol-5-yloxy}-pyridine- 2-carboxylic acid methylamide 551@2.62 min 92

4-[1-(3-Trifluoromethyl- phenylmethanesulfonyl)-2,3-dihydro-1H-indol-5-yloxy]-pyridine-2- carboxylic acid methylamide 492 @2.61 min93

4-{1-[5-(2-Methylsulfanyl-pyrimidin- 4-yl)-thiophene-2-sulfonyl]-2,3-dihydro-1H-indol-5-yloxy}-pyridine- 2-carboxylic acid methylamide 540.2@2.77 min 94

4-{1-[5-({[1-(4-Chloro-phenyl)- methanoyl]-amino}-methyl)-thiophene-2-sulfonyl]-2,3-dihydro- 1H-indol-5-yloxy}-pyridine-2-carboxylic acid methylamide 583 @2.34 min 95

4-[1-(4-Benzenesulfonyl-thiophene-2- sulfonyl)-2,3-dihydro-1H-indol-5-yloxy]-pyridine-2-carboxylic acid methylamide 566 @2.28 min 96

4-[1-(5-Chloro-1,3-dimethyl-1H- pyrazole-4-sulfonyl)-2,3-dihydro-1H--indol-5-yloxy]-pyridine-2-carboxylic acid methylamide 462 @2.05 min 97

4-{1-[5-(5-Trifluoromethyl-pyridine- 2-sulfonyl)-thiophene-2-sulfonyl]-2,3-dihydro-1H-indol-5-yloxy}- pyridine-2-carboxylic acid methylamide625 @2.43 min 98

4-[1-(Bis-trifluoromethyl- phenylmethanesulfonyl)-2,3-dihydro-1H-indol-5-yloxy]-pyridine-2- carboxylic acid methylamide 560 @2.46 min99

4-{1-[5-(Methyl-trifluoromethyl-2H- pyrazol-3-yl)-thiophene-2-sulfonyl]-2,3-dihydro-1H-coxy}-pyridine-2- carboxylic acid methylamide 464 @2.56min

Example 100

5-[Methyl-(2-methylcarbamoyl-pyridin-4-yl)-methyl-amino]-2,3-dihydro-indole-1-carboxylicacid (3′-trifluoromethyl-phenyl)-amide

a) 4-(1-Acetyl-2,3-dihydro-1H-indol-5-ylamino)-pyridine-2-carboxylicacid methylamide. A mixture of 4 chloro-pyridine-2-carboxylic acidmethyl amide (Example 1(a) 340 mg, 2 mmol) and1-acetyl-2,3-dihydro-5-aminoindole (350 mg, 2 mmol) in isopropanol (5ml) with ethereal HCl added (0.5 mL) was heated for 5 days at 85° in asealed tube. LC/ms showed complete reaction. The reaction mixture wasdiluted with EtOAc then treated with solid NaHCO3 and filtered. Thefiltrate was concentrated to give a green-brown solid which wastriturated with ether to afford the title compound. (699 mg, 100%) LC-MS(m/e)=311 [M+H]⁺.

b)4-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-methyl-amino]-pyridine-2-carboxylicacid methylamide.4-(1-Acetyl-2,3-dihydro-1H-indol-5-ylamino)-pyridine-2-carboxylic acidmethylamide (93 mg, 0.3 mmol) and CsCO₃ (600 mg) were stirred for 10 minin DMF at rt then MeI was injected (28 uL, 0.45 mmol). After 1 hr. tlcshowed starting material present so an additional 10 uL of MeI wasadded. The reaction was stirred at rt for 18 h then diluted with waterand extracted (×3) with EtOAc. The organic extracts were washed withwater (×2) and brine. After drying (MgSO₄) the solvent was removed underreduced pressure to afford a yellow gum which was triturated with hotEt₂O, cooled and diluted with hexanes to afford a white solid (59 mg,61%). LC-MS (m/e)=325[M+H]⁺@1.3 min.

c) 4-[(2,3-dihydro-1H-indol-5-yl)-methyl-amino]-pyridine-2-carboxylicacid methylamide. The4-[(1-Acetyl-2,3-dihydro-1H-indol-5-ylmethyl-amino]-pyridine-2-carboxylicacid methylamide (59 mg, 0.182 mmol) in 2N HCl (3 ml) was stirred at 85°for 3 h. After cooling to rt the acidic solution was treated with 1 NNaOH until pH=14. The white solid which had formed was extracted intoEtOAc and dried (MgSO₄). Evaporation of the solvent afforded the desiredproduct (49.7 mg, 97%) which was used in the next reaction withoutfurther purification.

d)5-[Methyl-(2-methylcarbamoyl-pyridin-4yl)-methyl-amino]-2,3-dihydro-indole-1-carboxylic-acid(3′-trifluoromethyl-phenyl)-amide. To a solution of2-fluoro-5-trifluoromethyl-phenylisocyanate (40.0 mg, 0.212 mmol) indichloromethane (2.0 mL) was addedmethyl-4-(2,3-dihydro-1-H-indol-5-methyl-amino)-pyridine-2-carboxylicacid methylamide (50 mg, 0.177 mmol) at rt. The reaction was stirredovernight at rt. Hplc confirmed complete reaction. The crude reactionmixture was chromatographed on reverse phase column eluting 10%-70%acetonitrile/0.1% TFA water affording after concentration andevaporation a bright yellow solid.(33 mg, 40%) LC-MS (m/e)=470.2 [M+H]⁺.

Example 1016-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3,4-trihydro-quinoline-1-carboxylicacid (3′-trifluoromethyl-phenyl)-amide

a) 4-(1,2,3,4-Tetrahydroquinoline-6-yloxy)-pyridine-2-carboxylic acidmethylamide. 6-Hydroxy-1,2,3,4-tetrahydroquinoline (149 mg, 1.0 mmol)which may be prepared by the method as described by Hoenel et al inJ.Chem.Soc.Perkin Tralls.I, 1933-1939 (1980), was dissolved in DMF (2ml) and treated at rt for 5 min with potassium t-butoxide (160 mg, 1.43eq) followed by addition of 4-Chloro-pyridine-2-carboxylic acidmethylamide (171 mg, 1.0 mmol). This mixture was under microwaveirradiation for 20 min at 160° C. in a Personal Chemistry synthesizer.The reaction mixture was partitioned between ethyl acetate and water andthe aqueous extracted with EtOAc (×4). The combined extracts were washedwith water (×3) and brine, then dried (Na₂SO₄) and evaporated underreduced pressure. The residue was purified by flash columnchromatography on the silica gel (hexane/EtOAC/CH₂Cl₂ 1:2:1) to affordthe title compound as an off-white solid. (239 mg, 84%) LC-MS (m/e)=284[M+H]⁺.

b)6-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3,4-trihydro-quinoline-1-carboxylicacid (3′-trifluoromethyl-phenyl)-amide. A solution of3-trifluoromethyl-phenylisocyanate (61 μL, 0.40 mmol) and4-(1,2,3,4-tetrahydroquinoline-6-yloxy)-pyridine-2-carboxylic acidmethylamide (57 mg, 0.20 mmol) in DMF was stirred at rt overnight, andconcentrated under the reduced pressure. The residue was purified byflash column chromatography on the silica gel (hexane/EtOAC 1:1) toafford the title compound as a white solid. (60 mg, 64%) LC-MS (m/e)=471[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=5.6 Hz, 1H), 8.2 (br s,1H), 7.77 (m, 2H), 7.63 (d, J=9.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.33 (d,J=7.6 Hz, 1H), 7.12 (m, 2H), 7.02-7.00 (m, 2), 3.89 (t, J=6.3 Hz, 2H),3.05 (d, J=5.1 Hz, 3H), 2.83 (t, J=6.6 Hz, 2H), 2.05 (m, 2H).

Example 1026-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3,4-trihydro-quinoline-1-carboxylicacid (3′-trifluoromethyl-4′-chloro-phenyl)-amide

Following the procedure of Example 53(b), except substituting4-chloro-3-trifluoromethyl-phenylisocyanate for3-trifluoromethyl-phenylisocyanate, the title compound was prepared as awhite solid (30 mg, 70%). LC-MS (m/e)=505/507 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.43 (d, J=5.6 Hz, 1H), 8.06 (m, 1H), 7.82 (d, J=2.5 Hz, 1H),7.70 (s, 1H), 7.66-7.63 (m, 1H), 7.44-7.34 (m, 3H), 7.11-7.08 (m, 1H),7.03-7.00 (m, 3), 3.87 (t, J=6.3 Hz, 2H), 3.02 (d, J=5.1 Hz, 3H), 2.85(t, J=6.7 Hz, 2H), 2.03 (m, 2H).

Example 1036-(2-Methylcarbamoyl-pyridin-4-yloxy)-2,3,4-trihydro-quinoline-1-carboxylicacid (3′,4′-difluoro-phenyl)-amide

Following the procedure of Example 53(b), except substituting(3,4-difluoro-phenylisocyanate for 3-trifluoromethyl-phenylisocyanate,the title compound was prepared as a white solid (46 mg, 81%). LC-MS(m/e)=439 [M+H]⁺. 1H NMR (400 MHz; CDCl₃) δ 8.35 (d, J=5.6 Hz, 1H), 7.98(m, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.47 (ddd, J=12.4, 7.1, 2.5 Hz, 1H),7.29 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 7.02-6.87 (m, 5H), 3.76 (t, J=6.3Hz, 2H), 2.94 (d, J=5.1 Hz, 3H), 2.68 (t, J=6.7 Hz, 2H), 1.92 (m, 2H).

Biological Data

Compounds are tested for TIE-2 kinase and VEGFR kinase inhibitionactivity according to one or more of the following methods.

TIE-2 Enzyme Assay (TIE2-E)

The TIE-2 enzyme assay uses the LANCE method (Wallac) and GST-TIE2,baculovirus expressed recombinant constructs of the intracellulardomains of human TIE2 (amino acids 762-1104, GenBank Accession #L06139)tagged by GST). The method measures the ability of the purified enzymesto catalyse the transfer of the γ-phosphate from ATP onto tyrosineresidues in a biotinylated synthetic peptide, D1-15(biotin-C₆-LEARLVAYEGWVAGKKKamide). This peptide phosphorylation isdetected using the following procedure: for enzyme preactivation,GST-TIE2 is incubated for 30 mins at room temperature with 2 mM ATP, 5mM MgCl2 and 12.5 mM DTT in 22.5 MM HEPES buffer (pH7.4). PreactivatedGST-TIE2 is incubated for 30mins at room temperature in 96 well plateswith 1 uM D1-15 peptide, 80 uM ATP, 10 mM MgCl₂, 0.1 mg/ml BSA and thetest compound (diluted from a 10 mM stock in DMSO, final DMSOconcentration is 2.4%) in 1 mM HEPES (pH7.4). The reaction is stopped bythe addition of EDTA (final concentration 45 mM). Streptavidinlinked-APC (allophycocyanin, Molecular Probe) and Europium-labeledanti-phosphorylated tyrosine antibody (Wallac) are then added at thefinal concentration of 17 ug/well and 2.1 ug/well, respectively. The APCsignal is measured using an ARVO multilabel counter. (Wallac BertholdJapan). The percent inhibition of activity is calculated relative toblank control wells. The concentration of test compound that inhibits50% of activity (IC₅₀) is interpolated using nonlinear regression(Levernberg-Marquardt) and the equation, y=Vmax (1−x/(K+x))+Y2, where“K” is equal to the IC₅₀. The IC₅₀ values are converted to pIC₅₀ values,i.e., -log IC₅₀ in Molar concentration.

TIE-2 Enzyme Assay (TIE2-E2

The TIE-2 enzyme assay uses the LANCE method (Wallac) and GST-TIE2,baculovirus-expressed recombinant constructs of the intracellulardomains of human TIE2 (amino acids 762-1104, GenBank Accession #L06139)tagged by GST). The method measures the ability of the purified enzymesto catalyse the transfer of the γ-phosphate from ATP onto tyrosineresidues in a biotinylated synthetic peptide, D1-15(biotin-C₆-LEARLVAYEGWVAGKKKamide). This peptide phosphorylation isdetected using the following procedure: for enzyme preactivation,GST-TIE2 is incubated for 2 hours at room temperature with 80 μM ATP, 10mM MgCl₂, 0.1 mg/ml BSA, 0.01% Tween 20 and 1 mM DTT in 100 mM HEPESbuffer (pH7.4). 5 nM preactivated GST-TIE2 is incubated for 2 hours atroom temperature in 96 well plates with 1 uM D1-15 peptide, 80 uM ATP,10 mM MgCl12, 0.1 mg/ml BSA, 0.01% Tween 20 and titrated test compound(diluted from a 10 mM stock in DMSO, final DMSO concentration is 2.4%)in 100 mM HEPES (pH7.4). The reaction is stopped by the addition of EDTA(final concentration 45 mM). Streptavidin linked-APC (allophycocyanin,PerkinElmer) and europium-labeled anti-phosphotyrosine antibody(PerkinElmer) are then added at the final concentration of 8 nM and 1nM, respectively. The APC signal is measured using an Wallac Multilabel1420 counter. (Wallac Berthold Japan). The percent inhibition ofactivity is calculated relative to blank control wells. Theconcentration of test compound that inhibits 50% of activity (IC₅₀) isinterpolated using nonlinear regression (Levernberg-Marquardt) and theequation, y=Vmax (1−x/(K+x))+Y2, where “K” is equal to the IC₅₀. TheIC₅₀ values are converted to pIC₅₀ values, i.e., -log IC₅₀ in Molarconcentration.

TIE-2 Autophosphorylation assay (TIE2-C) The TIE-2 autophosphorylationassay uses an ELISA method and a TIE2 intracellular domain/c-fmsextracellular domain (TIE2/c-fms) chimeric protein expressing mouse 3T3cell line. This assay measures the autophosphorylation level of TIE2protein expressed in cells. The cells are cultured in 96 well plates andgrown in high glucose DMEM containing 10% serum at 37° C. in ahumidified 10% CO2, 90% air incubator. On the day of the assay, theserum containing medium is removed from the cells and replaced withserum free medium for one hour. The test compound (diluted from a 10 mMstock in DMSO, fmal DMSO concentration is 0.1%) is incubated withTIE2/c-fms expressing cells for 30 minutes in serum free DMEM. Intrinsiccellular dephosphorylation of the receptor is blocked by the addition ofthe tyrosine phosphatase inhibitor, sodium orthovanadate, from a 100 mMaqueous stock to a final concentration of 1 mM. The culture media isremoved by aspiration and the cells incubated for 30 to 60 mins on icewith lysis buffer containing 137 mM NaCl, 2 mM EDTA, 10% glycerol, 1 mMsodium ortho vanadate, 1× tyrosine phosphatase inhibitor cocktail(Sigma) and complete protease inhibitor cocktail (Roche) in 20 mMTris-HCl (pH8.0). The cell extracts are transferred into Rat anti-c-fmsantibody (Zymed—clone 12-2d6)(2.5 mg/ml) coated 96 well plates andincubated for 12 hrs at 4 degrees. The extracts are removed byaspiration and the plate, washed in a buffer comprising PBS, 0.05%Tween-20, 0.05% NP-40 and 5% SuperBlock (Pierce) followed by incubationwith an HRP (horseradish peroxidase) conjugated anti-phosphotyrosineantibody, (Upstate Biotech) The plates are again washed with theaforementioned wash buffer and the colorimetric HRP substrate, TMB isadded. The reaction progresses for 90 seconds and is stopped with theaddition of 2M H₂SO₄. The optical density at 450 nm derived from HRPcatalyzed TMB is measured with a plate reader capable of reading at theappropriate wavelength (e.g. SpectroMax from Molecular Dynamics). Thepercent inhibition of activity is calculated relative to non-vanadatetreated control wells. The concentration of test compound that inhibits50% of activity (IC₅₀) is interpolated using nonlinear regression(Levernberg-Marquardt) and the equation, y=Vmax (1−x/(K+x))+Y2, where“K” is equal to the IC₅₀.

Tie2 Fluorescence Polarization Kinase Activity Assay: (TIE2-FP)

Activation of recombinant Tie2 activation: Recombinant GST-Tie2 isactivated by incubating the enzyme in 20 mM Tris-HCl, pH 7.5, 12 mMMgCl₂, 100 mM NaCl, 20 μM sodium vanidate, 1 mM DTT and 300 μM ATP atroom temperature for 2 hours. The activation mixture is then passedthrough a NAP-25 desalting column (Pharmacia Biotech cat. no.17-0852-02) to remove the free ATP. The activated enzyme is stored asaliquots at −80° C. in 20 mM Tris-HCl, pH 7.5 and 100 mM NaCl.

Assay conditions: The final assay conditions are 50 mM HEPES, pH 7.5, 5%DMSO (when screening compounds), 200 μM ATP, 5 mM MgCl₂, 1 M DTT, 50 μMsodium vanidate, 1 nM activated enzyme, and 200 μM peptide. IC₅₀'s ofcompounds are measured under subsaturating ATP (200 μM) and varyingconcentrations of activated Tie2 and peptide substrate (RFWKYEFWR-OH; MW1873 Da, TFA salt). Panvera Anti-phosphotyrosine antibody (Cat#P2840)and PTK Green Tracer (Cat#P2842) are used to detect the phosphorylatedpeptide. Polarization is measured on a TECAN Polarion in 138-secondcycles for 30 minutes at room temperature. IC₅₀'s are then determinedfrom the % polarization using normal calculation methods. The IC₅₀values are converted to pIC₅₀ values, i.e., -log IC₅₀ in Molarconcentration.

VEGF-R2 enzyme assay (VEGF-E): The VEGF enzyme assay uses the LANCEmethod (Wallac) and GST-VEGFR2, baculovirus expressed recombinantconstructs of the intracellular domains of human TIE2 tagged by GST. Themethod measures the ability of the purified enzymes to catalyse thetransfer of the γ-phosphate from ATP onto tyrosine residues in abiotinylated synthetic peptide, (biotin-aminohexyl-EEEEYFELVAKKKK-NH2).This peptide phosphorylation is detected using the following procedure:GST-VEGFR2 is incubated for 40-60 mins at room temperature with 75 uMATP, 5 mM MgCl2, 0.1 mM DTT, 0.1 mg/mL BSA and the test compound(diluted from a 10 mM stock in DMSO for desired concentration) in 100 mMHEPES buffer. The reaction is stopped by the addition of EDTA (finalconcentration 50 mM). Streptavidin linked-APC (allophycocyanin,Molecular Probe) and Europium-labeled anti-phosphorylated tyrosineantibody (Wallac) are then added at the fmal concentration of 15 nM and1 nM, respectively. The APC signal is measured using an ARVO multilabelcounter (Wallac Berthold, Japan). The percent inhibition of activity iscalculated relative to blank control wells. The concentration of testcompound that inhibits 50% of activity (IC₅₀) is interpolated usingnonlinear regression (Levernberg-Marquardt) and the equation,y=V_(max)(1−x/(K+x))+Y2, where “K” is equal to the IC₅₀. The IC₅₀ valuesare converted to pIC₅₀ values, i.e., -log IC₅₀ in Molar concentration.

VEGF-R2 enzyme assay (VEGF-E2): The VEGF enzyme assay uses the LANCEmethod (Wallac) and GST-VEGFR2, baculovirus expressed recombinantconstructs of the intracellular domains of human TIE2 tagged by GST. Themethod measures the ability of the purified enzymes to catalyse thetransfer of the γ-phosphate from ATP onto tyrosine residues in abiotinylated synthetic peptide, (biotin-aminohexyl-EEEEYFELVAKKKK-NH2).This peptide phosphorylation is detected using the following procedure:GST-VEGFR2 is incubated for 40-60 mins at room temperature with 75 uMATP, 5 mM MgCl₂, 0.1 mM DTT, 0.1 mg/mL BSA and the test compound(diluted from a 10 mM stock in DMSO for desired concentration) in 100 mMHEPES buffer. The reaction is stopped by the addition of EDTA (finalconcentration 50 mM). Streptavidin linked-APC (allophycocyanin,Molecular Probe) and Europium-labeled anti-phosphorylated tyrosineantibody (Wallac) are then added at the final concentration of 15 nM and1 nM, respectively. The APC signal is measured using an ARVO multilabelcounter (Wallac Berthold, Japan). The percent inhibition of activity iscalculated relative to blank control wells. The concentration of testcompound that inhibits 50% of activity (IC₅₀) is interpolated usingnonlinear regression (Levernberg-Marquardt) and the equation,y=V_(max)(1−x/(K+x))+Y2, where “K” is equal to the IC₅₀. The IC₅₀ valuesare converted to pIC₅₀ values, i.e., -log IC₅₀ in Molar concentration.

VEGF-friven cellular proliferation assay: BrdU incorporation assay(VEGF-C)

Human umbilical cord endothelial cells (HUVEC, Clonetics, CC2519) arepassaged in Type I collagen-coated 100-mm petri dishes in EGM-MV medium(Clonetics, CC3125) at 37 C in a humidified 5% CO2, 95% air incubator.(HUVEC passaged more than 6 times in vitro are discarded and notsubjected to assaying.) The cells are harvested using trypsin/EDTA,counted using a haemocytometer and plated at 5000 cells/well in a TypeI-collagen coated 96-well plate (Becton Dickinson, 354407) in M199medium (Gibco BRL, 12340-030) containing 5% FBS (Hyclone, A 1115-L) andgentamicin (at 50 ug/ml, Gibco BRL). After incubation overnight at 37°C., the media are replaced with 100 ul of M199 serum-free mediumcontaining compounds at various concentrations with 0.6% DMSO andgentamicin. The compounds are diluted in serum-free M199 medium from 10mM stock solutions prepared in 100% DMSO. After a 30 min incubation at37° C., the cells are fed with 100 ul of serum-free M199 mediumcontaining gentamicin, 0.2% culture-grade bovine serum albumin (BSA,Sigma A1993) and 20 mg/ml of VEGF (R&D systems, 293-VE) or 0.6 mg/ml ofbasic FGF (R&D systems, 233-FB), and cultured at 37° C. for another 24h. The cells are pulsed with bromodeoxyuridine (BrdU at 10 uM inserum-free M199) at 37° C. for an additional 24 h. The incorporation ofBrdU into the proliferating HUVEC are analyzed using BrdU CellProliferation ELISA (Roche Molecular Biochemicals, 1647229) according tothe manufacturer's protocols. The optical density at 450 nm is measuredwith a multilabel counter (ARVO SX, Wallac). The percent inhibition ofcell growth is calculated relative to blank control wells. Theconcentration of test compound that inhibits 50% of cell growth (IC₅₀)is interpolated using nonlinear regression (Levernberg-Marquardt) andthe equation, y=Vmax (1−x/(K+x))+Y2, where “K” is equal to the IC₅₀. TheIC₅₀ values are converted to pIC₅₀ values, i.e., -log IC₅₀ in Molarconcentration.

VEGFR-3—Homogenous Time-Resolved Fluorescence Assay (VEGFR-3-HTRF)

This assay assesses Vascular Endothelial Growth Factor 3 (VEGFR3)tyrosine kinase inhibitory activity in substrate phosphorylation assays.The assay examines the ability of small molecule organic compounds toinhibit the tyrosine phosphorylation of a peptide substrate.

The substrate phosphorylation assays use the VEGFR3 catalytic domain,which is expressed in Sf. 9 insect cells as an amino-terminal GST-taggedfusion protein. The catalytic domain of human VEGFR3 (AA residues#819-1298 based upon GenBank Accession #XM003852) is cloned by PCR fromhuman Placenta Marathon Ready cDNA (Clontech). The PCR product issubcloned into pFastBacl vector containing an N-terminal GST tag. Theresulting pFB/GST/VEGFR3icd vector is used to generate a recombinantbaculovirus for protein expression. The VEGFR3 catalytic domaintranslated sequence is: MSPILGYWKI KGLVQPTRLL LEYLEEKYEE HLYERDEGDKWRNKKFELGL EFPNLPYYID GDVKLTQSMA IIRYIADKHN MLGGCPKERA EISMLEGAVLDIRYGVSRIA YSKDFETLKV DFLSKLPEML KMFEDRLCHK TYLNGDHVTH PDFMLYDALDVVLYMDPMCL DAFPKLVCFK KRIEATPQID KYLKSSKYIA WPLQGWQATF GGGDHPPKSDLLVPRGSPEF KGLPGEVPLE EQCEYLSYDA SQWEFPRERL HLGRVLGYGA FGKVVEASAFGIHKGSSCDT VAVKMLKEGA TASEQRALMS ELKILIHIGN HLNVVNLLGA CTKPQGPLMVIVEFCKYGNL SNFLRAKRDA FSPCAEKSPE QRGRFRAMVE LARLDRRRPG SSDRVLFARFSKTEGGARRA SPDQEAEDLW LSPLTMEDLV CYSFQVARGM EFLASRKCIH RDLAARNILLSESDVVKICD FGLARDIYKD PDYVRKGSAR LPLKWMAPES IFDKVYTTQS DVWSFGVLLWEIFSLGASPY PGVQINEEFC QRLRDGTRMR APELATPAIR RIMLNCWSGD PKARPAFSELVEILGDLLQG RGLQEEEEVC MAPRSSQSSE EGSFSQVSTM ALHIAQADAE DSPPSLQRHSLAARYYNWVS FPGCLARGAE TRGSSRMKTF EEFPMTPTTY KGSVDNQTDS GMVLASEEFEQIESRHRQES GFR

Autophosphorylation allows enzymes to be fully activated prior toaddition to peptide substrates. The assays are performed using enzymethat has been activated by autophosphorylation via preincubation inbuffer with ATP and magnesium. Activated enzyme is then diluted andadded to titrated compound and the substrate mix.

200 nM VEGFR3 enzyme is activated for 45 minutes at room temperature byincubating the enzyme in buffer containing 100 mM HEPES (pH7.2), 75 μMATP, 0.3 mM DTT, 0.1 mg/mL BSA, and 10 mM MgCl₂. After activation,VEGFR3 is diluted 100-fold into 2× dilution buffer: 200 mM HEPES (pH7.5), 0.2 mg/mL BSA, 0.6 mM DTT. 20 μL of the diluted enzyme mix isadded to 20 μL of 2× substrate mix (150 μM ATP, 20 mM MgCl₂ 0.72 μMbiotinylated peptide) in the assay plates. Final assay conditions are:100 mM HEPES (pH 7.2), 75 μM ATP, 20 mM MgCl₂, 0.1 mg/mL BSA, 0.3 mMDTT, 0.36 μM biotinylated peptide, and 1 nM VEGFR3 enzyme. Assay platesare incubated for 1.5 hours at room temperature before the addition of30 μL 100 mM EDTA to the wells to stop the enzymatic reaction. 40μL/well of HTRF mix are then added to the assay plates for the detectionof phosphorylated substrate. Final assay concentrations are: 100 mMHEPES (pH7.2), 0.1 mg/mL BSA, 15 nM streptavidin-labeled allophycocyanin(PerkinElmer), and 1 nM europium-labeled anti-phosphotyrosine antibody(PerkinElmer). Assay plates are left unsealed and are counted in aWallac Multilabel Counter 1420 (PerkinElmer).

The data for dose responses are plotted as % Control calculated with thedata reduction formula (100)(U1-C2)/(C1-C2) versus concentration ofcompound where U is the unknown value, C1 is the average control valueobtained for DMSO, and C2 is the average control value obtained for 0.1M EDTA. Data are fitted to the curve described by: y=((Vmax)(x)/(K+x))where Vmax is the upper asymptote and K is the IC50.

The compounds of Examples 3, 4, 6 and 7 demonstrated inhibition of TIE2kinase with an IC₅₀ of less than 250 nm. The compounds of Examples 1-8demonstrated inhibition of VEGFR2 kinase with an IC₅₀ of less than 250nm. The compound of Example 8 demonstrated inhibition of Raf kinase withan IC₅₀ of less than 250 nm.

1. A compound of Formula I:

wherein: n is an integer of 1, 2, or 3; R^(A) is —CONHR¹, —NHR¹,—NHCOR¹, —NHCONHR¹, —NHCO₂R¹, —NHSO₂R¹ or —NHSO₂NHR¹; wherein R¹ ishydrogen or an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, aryl-C₁-C₄alkyl- or heteroaryl-C₁-C₄ alkyl- group, where said optionallysubstituted R¹ group is optionally substituted with one or moresubstituents independently selected from halogen, —R^(1a), —OR^(1a),—SR^(1a), —SO₂R^(1c)—NR^(1a)R^(1b), cyano, nitro, —COR^(1c), —CO₂R^(1a),—NR^(1b)COR^(1a), —CONR^(1a)R^(1b), —NR^(1b)SO₂R^(1c), and—SO₂NR^(1a)R^(1b), where R^(1a) is hydrogen or an optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl,heteroaryl, heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇ cycloalkyl-C₁-C₄alkyl-, heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-, heteroaryl-C₂-C₄ alkenyl-,heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄ alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄alkynyl-, heteroaryl-C₂-C₄ alkynyl-, or heterocycyl-C₂-C₄ alkynyl-group, R^(1b) is hydrogen or unsubstituted C₁-C₄ alkyl, and R^(1c) is anoptionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇cycloalkyl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄alkyl-, aryl-C₂-C₄ alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-,heteroaryl-C₂-C₄ alkenyl-, heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkynyl-, heteroaryl-C₂-C₄ alkynyl-, orheterocycyl-C₂-C₄ alkynyl- group, where each optionally substitutedR^(1a) group and R^(1c) group is independently optionally substitutedwith one or more substituents independently selected from C₁-C₄ alkyl,C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halogen, —OH, —NH₂,—N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), cyano, nitro, oxo,—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), -C(O)C₁-C₄ alkyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄alkyl), and —NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ alkyl isunsubstituted C₁-C₄ alkyl, or R^(1a) and R^(1b), together with thenitrogen atom to which they are attached, form an optionally substitutedheterocycyl or heteroaryl ring which optionally contains one or moreadditional heteroatom moieties selected from O, S, SO, SO₂, N and N→O,wherein said optionally substituted heterocycyl or heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄haloalkyl, halogen, —OH, —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), cyano, nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄haloalkyl, —SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄ alkyl), and —NHS(O)₂(C₁-C₄haloalkyl), where said C₁-C₄ alkyl is unsubstituted C₁-C₄ alkyl, X isNR², O, S, SO or SO₂, wherein R is hydrogen or an optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl,heteroaryl, heterocyclyl, aryl-C₁-C₄ alkyl- or heteroaryl-C₁-C₄ alkyl-group, where said optionally substituted R² group is optionallysubstituted with one or more substituents independently selected fromhalogen, —R^(2a), —OR^(2a), —SR^(2a), —SO₂R^(2c)—NR^(2a)R^(2b), cyano,nitro, —COR^(2c), —CO₂R^(2a), —NR^(2b)COR^(2a), —CONR^(2a)R^(2b),—NR^(2b)SO₂R^(2c), and —SO₂NR^(2a)R^(2b), where R²a is hydrogen or anoptionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇cycloalkyl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄alkyl-, aryl-C₂-C₄ alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-,heteroaryl-C₂-C₄ alkenyl-, heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkynyl-, heteroaryl-C₂-C₄ alkynyl-, orheterocycyl-C₂-C₄ alkynyl- group, R^(2b) is hydrogen or unsubstitutedC₁-C₄ alkyl, and R^(2c) is an optionally substituted C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl,heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇ cycloalkyl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄ alkenyl-,C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-, heteroaryl-C₂-C₄ alkenyl-,heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄ alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄alkynyl-, heteroaryl-C₂-C₄ alkynyl-, or heterocycyl-C₂-C₄ alkynyl-group, where each optionally substituted R^(2a) group and R^(2c) groupis independently optionally substituted with one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl,—OC₁-C₄ haloalkyl, halogen, —OH, —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), cyano, nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl,—CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ haloalkyl,—OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄ alkyl), and—NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ alkyl is unsubstituted C₁-C₄alkyl, or R^(2a) and R^(2b), together with the nitrogen atom to whichthey are attached, form an optionally substituted heterocycyl orheteroaryl ring which optionally contains one or more additionalheteroatom moieties selected from O, S, SO, SO₂, N and N→O, wherein saidoptionally substituted heterocycyl or heteroaryl ring is optionallysubstituted with one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halogen,—OH, —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), cyano, nitro,oxo, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl,—SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—NHS(O)₂(C₁-C₄ alkyl), and —NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄alkyl is unsubstituted C₁-C₄ alkyl, R^(B) is —CONHR³, —SO₂R³; —CO₂R³,—COC(R⁴R⁵)R³, wherein R³ is hydrogen or an optionally substituted C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl, heteroaryl,heterocyclyl, aryl-C₁-C₄ alkyl- or heteroaryl-C₁-C₄ alkyl- group, wheresaid optionally substituted R³ group is optionally substituted with oneor more substituents independently selected from halogen, —R^(3a),—OR^(3a), —SR^(3a), —SO₂R^(3c)—NR^(3a)R^(3b), cyano, nitro, —COR^(3c),—CO₂R^(3a), —NR^(3b)COR^(3a), —CONR^(3a)R^(3b), —NR^(3b)SO₂R^(3c), and—SO₂NR^(3a)R^(3b), where R^(3a) is hydrogen or an optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, C₃-C₇ cycloalkyl,heteroaryl, heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇ cycloalkyl-C₁-C₄alkyl-, heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄ alkyl-, aryl-C₂-C₄alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-, heteroaryl-C₂-C₄ alkenyl-,heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄ alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄alkynyl-, heteroaryl-C₂-C₄ alkynyl-, or heterocycyl-C₂-C₄ alkynyl-group, R^(3b) is hydrogen or unsubstituted C₁-C₄ alkyl, and R^(3c) is anoptionally substituted C,-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, aryl-C₁-C₄ alkyl-, C₃-C₇cycloalkyl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, heterocycyl-C₁-C₄alkyl-, aryl-C₂-C₄ alkenyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkenyl-,heteroaryl-C₂-C₄ alkenyl-, heterocycyl-C₂-C₄ alkenyl-, aryl-C₂-C₄alkynyl-, C₃-C₇ cycloalkyl-C₂-C₄ alkynyl-, heteroaryl-C₂-C₄ alkynyl-, orheterocycyl-C₂-C₄ alkynyl- group, where each optionally substitutedR^(3a) group and R^(3c) group is independently optionally substitutedwith one or more substituents independently selected from C₁-C₄ alkyl,C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halogen, —OH, —NH₂,—N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), cyano, nitro, oxo,—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C,-C₄ alkyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl, —SO₂(C₁-C₄ alkyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄alkyl), and —NHS(O)₂(C₁-C₄ haloalkyl), where said C₁-C₄ alkyl isunsubstituted C₁-C₄ alkyl, or R^(3a) and R^(3b), together with thenitrogen atom to which they are attached, form an optionally substitutedheterocycyl or heteroaryl ring which optionally contains one or moreadditional heteroatom moieties selected from O, S, SO, SO₂, N and N→O,wherein said optionally substituted heterocycyl or heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄haloalkyl, halogen, —OH, —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), cyano, nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄haloalkyl, —SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,SO₂NH(C₁-C₄ alkyl), —NHS(O)₂(C₁-C₄ alkyl), and —NHS(O)₂(C₁-C₄haloalkyl), where said C₁-C₄alkyl is unsubstituted C₁-C₄alkyl, and R⁴and R⁵ are independently selected from hydrogen and unsubstituted C₁-C₄alkyl, or R⁴ and R⁵, taken together with the carbon atom to which theyare attached, represent an optionally substituted 3-6-membered saturatedcarbocyclic ring, where said optionally substituted 3-6-membered ring issubstituted with one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halogen,—OH, —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), cyano, nitro,oxo, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —OC(O)C₁-C₄ haloalkyl,—SO₂(C₁-C₄ alkyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—NHS(O)₂(C₁-C₄ alkyl), and —NHS(O)₂(C₁-C₄ haloalkyl), where saidC₁-C₄alkyl is unsubstituted C₁-C₄alkyl., or a salt, solvate, orphysiologically functional derivative thereof.
 2. A compound accordingto claim 1, wherein n is 1 or
 2. 3. A compound according to claim 1,wherein X is O or NR2.
 4. A compound according to claim 1, having theformula:


5. A compound according to claim 1, having the formula:


6. A compound according to claim 1, wherein R^(A) is —CONHR¹, —NHCOR¹,or —NHSO₂R¹, where R¹ is C₁-C₆ alkyl, aryl, heteroaryl, heterocycyl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄ alkyl-,wherein said C₁-C₆ alkyl is optionally substituted with one ore moresubstituents independently selected from —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄alkyl), and —NH(C₁-C₄ alkyl), or said aryl, heteroaryl or heterocycyl orthe aryl, heteroaryl or heterocycyl moiety of said aryl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄ alkyl- is unsubstituted orsubstituted by one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl and halogen.
 7. A compound according toclaim 1, wherein R^(B) is —CONHR³ or —SO₂R³; where R³ is aryl orheteroaryl, wherein said aryl or heteroaryl is unsubstituted orsubstituted by one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,aryl, heteroaryl and heterocycyl.
 8. A compound according to claim 1,wherein R^(A) is —CONHR¹, where R¹ is C₁-C₆ alkyl, aryl, heteroaryl,heterocycyl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, orheterocycyl-C₁-C₄ alkyl-, wherein said C₁-C₆ alkyl is optionallysubstituted with one ore more substituents independently selected from—NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), and —NH(C₁-C₄ alkyl), or said aryl,heteroaryl or heterocycyl or the aryl, heteroaryl or heterocycyl moietyof said aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, or heterocycyl-C₁-C₄alkyl- is unsubstituted or substituted by one or more substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl and halogen. 9.A compound according to claim 1, wherein R^(B) is —CONHR , where R³ isaryl or heteroaryl, wherein said aryl or heteroaryl is unsubstituted orsubstituted by one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,aryl, heteroaryl and heterocycyl.
 10. A compound according to claim 1,wherein R^(A) is —CONHR¹, —NHCOR¹, —NHSO₂R¹, where R¹ is C₁-C₆ alkyl,aryl, heteroaryl, heterocycyl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄alkyl-, or heterocycyl-C₁-C₄ alkyl-, wherein said C₁-C₆ alkyl isoptionally substituted with one or more substituents independentlyselected from —NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), orsaid aryl, heteroaryl or heterocycyl or the aryl, heteroaryl orheterocycyl moiety of said aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,or heterocycyl-C₁-C₄ alkyl- is unsubstituted or substituted by one ormore substituents independently selected from C₁-C₄ alkyl, C₁-C₄haloalkyl and halogen., and R^(B) is —CONHR³ or —SO₂NHR³; where R³ isaryl or heteroaryl, wherein said aryl or heteroaryl is unsubstituted orsubstituted by one or more substituents independently selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,aryl, heteroaryl and heterocycyl; or a salt, solvate, or physiologicallyfunctional derivative thereof.
 11. A compound according to claim 10,wherein R¹ is methyl, ethyl, phenyl, benzyl, phenethyl, N,Ndiethylaminopropyl, N-methyl-piperidinyl, piperidinyl-ethyl,pyrrolidinyl-butyl, morpholino-ethyl, or morpholino-propyl; and R³ issubstituted phenyl or substituted isoxazolyl, where said phenyl orisoxazolyl is substituted by one or more substituents independentlyselected from F, Cl, CF₃, or tert-butyl; or a salt, solvate, orphysiologically functional derivative thereof.
 12. A compound accordingto claim 1 wherein n is 1 or 2; R^(A) is —CONHR¹, where R¹ is methyl,ethyl, phenyl, benzyl, phenethyl, N,N diethylaminopropyl,N-methyl-piperidinyl, piperidinyl-ethyl, pyrrolidinyl-butyl,morpholino-ethyl, or morpholino-propyl; X is O; and R^(B) is —CONHR³,where R³ is substituted phenyl or substituted isoxazolyl, where saidphenyl or isoxazolyl is substituted by one or more substituentsindependently selected from F, Cl, CF₃, or tert-butyl; or a salt,solvate, or physiologically functional derivative thereof.
 13. Acompound according to claim 1 wherein n is 1; R^(A) is —CONHR¹, where R¹is methyl, ethyl, phenyl, benzyl, phenethyl, N,N diethylaminopropyl,N-methyl-piperidinyl, piperidinyl-ethyl, pyrrolidinyl-butyl,morpholino-ethyl, or morpholino-propyl; X is O; and R^(B) is —CONHR³,where R³ is substituted phenyl or substituted isoxazolyl, where saidphenyl or isoxazolyl is substituted by one or more substituentsindependently selected from F, Cl, CF₃, or tert-butyl; or a salt,solvate, or physiologically functional derivative thereof.
 14. Apharmaceutical composition, comprising: a) a therapeutically effectiveamount of a compound according to claim 1, or a salt, solvate, or aphysiologically functional derivative thereof, and b) one or more ofpharmaceutically acceptable carriers, diluents and excipients, c) thecomposition optionally further comprising an additional agent: selectedfrom anti-neoplastic agents, agents which inhibit angiogenesis, or acombination thereof.
 15. A method of treating a mammal having a disordermediated by at least one of inappropriate TIE-2 kinase, VEGFR-2 kinase,VEGFR-3 kinase or Raf kinase activity comprising administering to saidmammal a therapeutically effective amount of a compound according toclaim 1, or a salt, solvate, or a physiologically functional derivativethereof.
 16. A method of treating a mammal having a cancer, comprisingadministering to said mammal a therapeutically effective amount of acompound according to claim 1, or a salt, solvate, or a physiologicallyfunctional derivative thereof, the method optionally further comprisingadministering a therapeutically effective amount of at least oneadditional anti-cancer therapy, for example, wherein the additionalanti-cancer therapy is administered before, concomitantly with, or afterthe administration of the compound according to claim 1, salt, solvateor physiologically functional derivative thereof.
 17. A method oftreating a mammal having a disease which is characterized by cellularproliferation in the area of disorders associated withneo-vascularization and/or vascular permeability in a mammal, comprisingadministering to said mammal a therapeutically effective amount ofcompound according to claim 1, or a salt, solvate, or a physiologicallyfunctional derivative thereof.
 18. A method of treating a mammal havinga disorder mediated by at least one of inappropriate TIE-2 kinase,VEGFR-2 kinase, or VEGFR-3 kinase activity, comprising administering tosaid mammal therapeutically effective amounts of: a) a compoundaccording to claim 1, or a salt, solvate or physiologically functionalderivative thereof, and b) an agent to inhibit growth factor receptorfunction, wherein the agent to inhibit growth factor receptor functionis selected from an agent that inhibits the function of platelet derivedgrowth factor receptor, the function of epidermal growth factorreceptor, the function of the erbB2 receptor, the function of the erbB4receptor, the function of a VEGF receptor, and/or the function of theTIE-2 receptor, wherein: i) the agent to inhibit growth factor receptorfunction inhibits the function of the epidermal growth factor receptorand the erbB2 receptor; ii) the agent to inhibit growth factor receptorfunction inhibits the function of at least two of the epidermal growthfactor receptor, the erbB2 receptor, and the erbB4 receptor; or iii) theagent to inhibit growth factor receptor function inhibits the functionof at least one of the VEGF receptor and the TIE-2 receptor.
 19. Amethod of treating a mammal having a disorder characterized byinappropriate angiogenesis, comprising administering to said mammal atherapeutically effective amount of a compound according to claim 1, ora salt, solvate or physiologically functional derivative thereof,wherein the inappropriate angiogenesis results from at least one ofinappropriate VEGFR-2 kinase, VEGFR-3 kinase, or TIE-2 kinase activity,and the method optionally further comprising administering atherapeutically effective amount of a VEGFR2 inhibitor.
 20. The methodaccording to claim 15, wherein the disorder is selected from cancer anddiseases afflicting mammals which are characterized by cellularproliferation and being in the area of disorders associated withneo-vascularization and/or vascular permeability.